Depression in adults: Clinical features and diagnosis

INTRODUCTION — 

Depression occurs along a continuum of severity, and depressive syndromes such as major depressive disorder are heterogeneous [1]. The multiple presentations of major depression stem in part from the several subtypes that have been identified and the many comorbid disorders that frequently occur.

This topic reviews the clinical features and diagnosis of depressive disorders in adults. The assessment of adults with suspected depression; epidemiology, neurobiology, treatment, prognosis, and course of illness of depression in adults; and the clinical features and diagnosis of depression in pediatric and older adult patients are discussed separately:

●(See "Approach to the adult patient with suspected depression".)

●(See "Major depression in adults: Epidemiology".)

●(See "Major depressive disorder in adults: Approach to initial management".)

●(See "Depression in adults: Course of illness".)

●(See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)

●(See "Diagnosis and management of late-life depression".)

DEFINITIONS OF DEPRESSION — 

The term "depression" can be used in multiple ways, which can confuse conversations about its clinical manifestations and diagnosis. Depression can refer to a mood state, syndrome, or psychiatric disorder (table 1) [2,3]. In this topic, "depressed mood" denotes a mood state, and "depression" or "depressive episode" denotes a syndrome. "Depressive disorder" or "major depression" denotes a psychiatric disorder, such as major depressive disorder or premenstrual dysphoric disorder [3].

CLINICAL FEATURES

Age of symptom onset — A first episode of major depressive disorder (MDD) can occur at any age, although a significant proportion of those with MDD will experience a first episode before age 30 years. In a representative sample of United States adults, the reported mean age at first episode was 29 years [4].

Symptoms and signs — Although individuals with depression can have very heterogeneous presentations [1,5], most patients with MDD have the following symptoms (table 2) [6]:

●Sad, irritable, or anxious mood

●Loss of pleasure in activities

●Impaired concentration and decision-making

●Worthlessness and inappropriate guilt

●Hopelessness

●Fatigue or loss of energy

●Sleep disturbances

Depression causes not just emotional but physical and cognitive symptoms, all of which can impair functioning. Severe, but less frequent, symptoms include suicidal thoughts and behaviors and psychotic features.

Emotional

●Depressed mood (dysphoria) – Depressed mood is a core symptom of depressive disorders [3]. Dysphoria can take many forms, such as feeling sad, hopeless, discouraged, "blue," or "down in the dumps." Some patients instead experience a sense of emotional numbness (ie, state they have no feelings) or feel "blah."

On examination, patients may appear sad or tearful, or they may exhibit a distinct lack of affect (eg, "flat" affect).

●Loss of interest or pleasure – Loss of interest or pleasure (anhedonia) in formerly pleasurable activities is a core symptom of MDD [3]. Patients experience events, hobbies, and activities as less interesting or fun or do not plan or look forward to activities that they previously enjoyed. They may report that "they don't care anymore." Anhedonia often manifests as social withdrawal; patients may withdraw from or lose interest in friends, family, and community. They may also experience decreased libido or interest in sex.

●Anger or irritability – In some individuals with depression, anger or irritability predominates over depressed mood. Increased and persistent annoyance, frustration, irritability, anger, or hostility occurs in roughly 50 percent of patients with major depression [7-9]. This presentation may occur more commonly in men and include anger attacks or aggression (eg, suddenly losing control and hurting someone or threatening to hurt someone) [10].

●Anxiety – Anxiety is a common symptom of depression that can manifest as excessive worry, restlessness, and muscle tension.

Some patients with anxiety and depression are classified as having anxious depression (table 3). (See 'Specific symptom constellations' below.)

Anxiety disorders can be comorbid with or mistaken for depression. (See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis".)

Physical (neurovegetative) — Physical, or neurovegetative, symptoms of depression include disturbances of sleep, appetite, energy, and psychomotor functioning. Most individuals with sleep and appetite disturbances experience insomnia and anorexia with weight loss; however, patients with atypical depression can have hypersomnia and hyperphagia with weight gain. (See 'Specific symptom constellations' below.)

Some studies suggest that women are more likely to endorse neurovegetative symptoms than men [11].

●Change in appetite or weight – Appetite and weight may decrease or increase in depressive disorders [3]. Some patients have to force themselves to eat, whereas others eat more and may crave specific foods (eg, junk food and carbohydrates).

●Sleep disturbance – Sleep disturbances commonly occur in depressive disorders [3]. Many patients with depression describe their sleep as nonrestorative and report difficulty getting out of bed in the morning. Specific sleep disturbances include:

•Initial insomnia – Difficulty getting to sleep

•Middle insomnia – Waking in the middle of the night, with difficulty returning to sleep

•Terminal insomnia – Waking earlier than usual and remaining awake

•Hypersomnia – Prolonged nighttime sleep, or daytime sleeping

●Fatigue or loss of energy – Individuals with depression often feel tired, exhausted, and listless; this is a core symptom of depression. They may need to rest during the day, experience heaviness in their limbs, or have difficulty initiating or completing activities.

●Psychomotor agitation or retardation – Psychomotor disturbances are less common than other symptoms and may indicate more severe depression [3,6]. Psychomotor disturbances are behaviors that are objectively observed by others and include agitation and retardation.

•Agitation – Psychomotor agitation involves excessive motor activity that is usually nonproductive, repetitive, and accompanied by a feeling of inner tension; examples include hand-wringing, pacing, and fidgeting. Agitation can also be observed in individuals with mania; however, people with mania typically experience a euphoric, expansive mood rather than the dysphoric mood that characterizes depression.

•Retardation – Psychomotor retardation involves generalized slowing of body movements, thinking, or speech. Patients may speak in a low volume with minimal inflection. They may speak less and demonstrate increased latency in answering questions.

Cognitive

●Feelings of worthlessness or excessive guilt – Depression distorts patients' self-perceptions, leading to beliefs that one is inadequate, inferior, worthless, or a failure [3]. This is a core feature of depression. Patients can experience a sense of inappropriate guilt, and they frequently misinterpret neutral events or minor setbacks as evidence of personal failings.

●Impaired concentration, memory, and decision-making – Depression can impair one's ability to think, concentrate, or make decisions [3,12]. Patients may complain of difficulties with memory and focus. On physical examination, they may appear distracted or inattentive. This is a core feature of depression.

Neurocognitive dysfunction in depression is generally mild, and its subjective symptoms often exceed objective findings. However, based on meta-analyses of neurocognitive studies, major depression causes clinically significant deficits in [13-15]:

•Attention

•Concentration

•Memory

•Executive function (eg, planning, problem-solving, reasoning, and impulsivity)

•Information processing (psychomotor) speed

•Cognitive flexibility (concept or set-shifting)

•Verbal fluency (listing as many words as possible from a category [eg, animals or fruits] in a set time, typically one minute)

•Social cognition (often referred to as "theory of mind"; the ability to infer the thoughts, intentions, or emotions of others based upon verbal and nonverbal communication such as facial expression, gestures, and body language)

Neurocognitive impairments can interfere with occupational functioning [13] and persist after patients have remitted from major depression [14,16]. Neurocognitive dysfunction is greater in patients who are less educated, older, or more severely depressed [13].

For most individuals with depression, especially young and middle-aged adults, cognitive symptoms are readily distinguished from those caused by delirium or dementia. However, in older patients, cognitive impairment from depression may be mistaken for neurodegenerative dementia ("pseudodementia" or "dementia of depression"). Although these cognitive changes often abate with successful depression treatment [3], some patients who initially present with major depression that includes memory difficulties ultimately develop neurodegenerative dementia.

Suicidal ideation and self-harm — Individuals with depression experience recurrent thoughts of death or suicide and may attempt suicide.

Patients may have occasional thoughts that life is not worth living or that others would be better off if the patient was dead. Such thoughts are distinct from suicidal ideation, which involves thoughts of wanting to die or commit suicide that can be frequent and intrusive. Such patients may plan for suicide, engage in preparatory acts (eg, selecting a time and location to commit suicide, purchasing a large amount of medication or a gun, or writing a suicide note), or attempt suicide.

Pervasive hopelessness (negative expectations for the future) can increase suicidality and lead patients to conclude that suicide is the only option to escape ceaseless, intense emotional pain. (See "Suicidal ideation and behavior in adults".)

Individuals with MDD with psychotic features may experience auditory hallucinations telling (commanding) them to commit suicide. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis", section on 'Psychotic features'.)

Some individuals commit acts of self-harm, such as superficially cutting or burning their skin, with the intention of mitigating psychologic pain rather than killing themselves (eg, nonsuicidal self-injury) [3]. Even if these patients deny suicidal intention, they are at increased risk of future suicide attempts and should be evaluated [17]. (See "Borderline personality disorder: Epidemiology, pathogenesis, clinical features, course, assessment, and diagnosis", section on 'Nonsuicidal self-injury'.)

Psychosis — Uncommonly, individuals with depression have symptoms of psychosis, such as delusions (false, fixed beliefs) or hallucinations. Clinical manifestations and the diagnosis of psychotic depression are discussed separately. (See 'Specific symptom constellations' below and "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis".)

Spectrum of illness — Depressive disorders occur across a spectrum of symptom severity [6,18-20]. Patients can present with relatively mild, subsyndromal symptoms or, at the extreme range of severity, exhibit severe functional impairment and/or catatonia. Severe depression is characterized by a higher number and intensity of depressive symptoms (table 4). Those with severe depression more commonly experience psychomotor slowing or agitation and other physical symptoms of depression, suicidal behaviors, psychotic features, and severe functional impairment [6].

Impact on function — Major depression causes disability, impacts functioning and quality of life, and can adversely affect the prognosis of general medical illnesses [21].

Major depression impairs functioning (work, household duties, relationships, and social roles), and the degree of impairment is proportional to symptom severity [22]. In the United States, functional limitations from major depression are comparable to those associated with arthritis, cardiovascular disease, diabetes, and stroke [23]. In a nationally representative sample from the United States, functioning among those with severe major depression was approximately one standard deviation below the national mean [4].

Most depressive episodes are associated with poor psychosocial and physical functioning and poor self-rated health [24-27]. As an example, in a nationally representative survey in the United States, over half of participants reported severely or very severely impaired psychosocial functioning [24]. Individuals with severe depression may become bedbound and fail to perform basic activities of living, including personal hygiene, toileting, and feeding.

COMORBIDITIES — 

Major depressive disorder (MDD) is often concurrent with other psychiatric or general medical disorders. Many psychiatric and other medical conditions increase the risk of developing major depression [3].

Psychiatric — Most individuals with major depression have psychiatric comorbidities, including anxiety and substance use disorders.

●Prevalence of psychiatric comorbidities – Reported prevalences of psychiatric comorbidities among individuals with major depression range from 69 to 76 percent [28,29]. Psychiatric comorbidities are also common among those with persistent depressive disorder [30].

Multiple comorbid psychiatric disorders can occur simultaneously in patients with major depression. In studies that surveyed individuals with major depression in the prior 12 months, 19 percent reported three or more comorbid disorders [31]. In another study of psychiatric clinic outpatients, those with major depression reported a mean of 1.4 coexisting psychiatric diagnoses [29].

●Types of comorbidities – Psychiatric disorders that occur more commonly in individuals with depressive disorders include anxiety disorders (eg, generalized anxiety disorder, panic disorder, social anxiety disorder), alcohol and other substance use disorders, posttraumatic stress disorder, obsessive-compulsive disorder, somatic symptom disorder, attention deficit hyperactivity disorder, and personality disorders.

In a nationally representative sample from the United States, adjusted odds ratios for comorbid psychiatric disorders among individuals with MDD ranged from two (for alcohol use disorder or specific phobia) to six (for generalized anxiety disorder) [4]. Personality disorders are common psychiatric comorbidities, occurring in approximately 50 percent of individuals with depressive disorders [32]. (See "Overview of personality disorders", section on 'Diagnosis'.)

●Comorbidity generally precedes depression onset – In close to 90 percent of patients, the comorbid psychiatric disorder precedes the onset of the depressive disorder [24,30].

●Worse prognosis – Any psychiatric comorbidity confers a worse prognosis for the depressive disorder than if the depression occurs in isolation [30,33,34].

Medical illnesses — General medical (ie, nonpsychiatric) illnesses are common in individuals with depression, and their coexistence with depression worsens the prognosis for both depression and the medical condition.

●Prevalence of medical comorbidities – Depression and other medical illnesses often occur together. A substantial proportion of individuals with depression have multiple medical comorbidities [35], which are often more common in those with depression than in the general population [31]. Approximately 70 percent of individuals with depression have at least one other medical condition [31,35]. In one population-based study in multiple countries, 28 percent of individuals with major depression had three or more conditions [31].

●Types of comorbidities – Medical conditions in those with depression are not confined to specific types of disease or organ systems [36,37]. As examples, depression is associated with coronary heart disease, diabetes mellitus, Parkinson disease, and stroke [38-44]. Depression in later life may increase the risk of subsequent cognitive decline [45-48]. (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment", section on 'Neuropsychiatric symptoms'.)

●Directionality of relationship – The directionality of the relationship between depression and medical comorbidities is not always clear (ie, whether depression increases the risk of developing future medical diseases or vice versa). For some diseases, the relationship seems bidirectional [49]. As an example, meta-analyses suggest that having depression is associated with a 32 percent increased risk of developing type 2 diabetes [50] and, conversely, that individuals with type 2 diabetes have a 24 percent increased relative risk of developing depression [51]. Similarly, a meta-analysis of 15 prospective observational studies (n>62,000 patients) found that depression at baseline increased the risk of subsequently becoming obese (odds ratio 1.6), and obesity at baseline increased the risk of depression at follow-up (odds ratio 1.6) [52].

•Effect of depression on medical comorbidities – Compared with those without depression, individuals with depression are at increased risk of other medical illnesses [53-55]. A study comparing primary care patients with (n>140,000) and without depression (n>1,280,000) found that those with depression were more likely to have each of the 32 comorbid conditions that were assessed, including asthma, cancer, chronic kidney disease, coronary heart disease, diabetes, epilepsy, heart failure, hypertension, inflammatory arthritis, multiple sclerosis, pain, Parkinson disease, thyroid disorders, and viral hepatitis [35].

Depression also worsens the outcome of comorbid medical conditions, including the risk of death and hospitalization. As an example, depression in older patients with diabetes increased the relative risk for all-cause mortality by at least 36 percent over a two-year period [49,55-58]. Similarly, depression is associated with an increased risk of cardiovascular mortality, with more severe depression symptoms being associated with higher risk [59,60]. The relationship between depression and cardiovascular disease is discussed in detail separately. (See "Psychosocial factors in acute coronary syndrome".)

The presence of depression is also associated with an increased risk of hospitalization for other medical illnesses. In a prospective multicohort study of 240,433 individuals, moderate to severe depression was associated with a 16 percent higher absolute risk of hospitalization over four years for 29 different medical illnesses: mainly endocrine, circulatory, and musculoskeletal diseases [49]. The excess risk of hospitalization for medical causes was greater than that for psychiatric and neurologic disorders combined (absolute risk increase of 1.7 percent).

•Effect of medical comorbidities on depression – Most chronic medical disorders, as well as many subacute and acute medical conditions and their treatments, increase the risk of subsequent depression [36]. The incidence of depression may be particularly high in neurologic diseases (eg, Parkinson disease, stroke, and traumatic brain injury) [44,61-63], cardiovascular disorders [64,65], cancer [66], and conditions involving immune and inflammatory mechanisms (eg, systemic lupus erythematosus [67]).

Although the presence of significant medical comorbidity worsens the prognosis of depression, treating depression in these patients is important and can improve self-rated health and functional status.

Diagnosing major depression in the context of other medical disorders is discussed elsewhere. (See "Approach to the adult patient with suspected depression", section on 'Evaluate for general medical illness'.)

ASSESSMENT

●When to suspect a depressive disorder – We suspect a depressive disorder when patients screen positive for depression, have depressed mood, or present with multiple unexplained somatic symptoms. This topic is discussed separately. (See "Approach to the adult patient with suspected depression", section on 'When to suspect a depressive disorder'.)

●Initial assessment – The initial assessment should determine if clinical depression exists, investigate medical conditions that might account for the patient's symptoms, and assess for risk of harm to self or others (algorithm 1). (See "Approach to the adult patient with suspected depression", section on 'Initial evaluation'.)

●Subsequent evaluation – If the initial assessment suggests a depressive disorder, we establish the diagnosis and evaluate for symptoms that need urgent evaluation or distinct management approaches (ie, symptoms of mania, psychosis, suicidal ideation or behavior, anxiety, and substance misuse). (See "Approach to the adult patient with suspected depression", section on 'Further assessment and differential diagnosis'.)

In primary care settings, many patients with suspected depression will not have a depressive disorder. These individuals should be evaluated for other causes of their mood or physical symptoms (table 5). (See "Approach to the adult patient with suspected depression", section on 'Patients without prominent depressive symptoms'.)

DIAGNOSIS

Use diagnostic criteria to diagnose depressive disorders — Depressive disorders are characterized by dysphoria (sad or irritable mood) (algorithm 2) [3]. Each depressive disorder likely represents an etiologically heterogeneous group of conditions with similar clinical manifestations. Using explicit criteria to diagnose depressive disorders may minimize overdiagnosis.

Multiple sets of diagnostic criteria exist for diagnosing depressive disorders. We recommend using the criteria in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) [3]. A reasonable alternative is the World Health Organization's International Classification of Diseases 11^th Revision [68].

Major depressive disorder

Establishing the diagnosis — Major depressive disorder (MDD) is a syndrome characterized by at least one episode of major depression (table 6) without a history of mania (table 7) or hypomania (table 8) [3]. The diagnosis of MDD is established with a clinical interview to determine if the patient meets specific diagnostic criteria. (See 'Diagnostic criteria' below.)

Each depressive symptom can occur in other psychiatric and general medical conditions, and none are pathognomonic for MDD [69]. Consequently, clinicians should consider whether an alternative diagnosis better fits the patient's clinical presentation. Clinicians should also consider whether the clinical presentation fits any of the subtypes of MDD. (See 'Specific symptom constellations' below.)

Diagnostic criteria — We typically use diagnostic criteria from the revised DSM-5-TR (table 6) [3]. Patients must have at least five of nine symptoms of depression for at least two consecutive weeks, and the symptoms must include either depressed mood or loss of interest or pleasure nearly every day. The symptoms cause significant distress or psychosocial impairment and are not the direct result of a substance or general medical condition.

Reliability and stability of diagnosis

●Test-retest reliability – Clinical assessments demonstrate fair to moderate test-retest reliability of DSM-5 diagnostic criteria for diagnosing MDD. Test-retest reliability is commonly utilized to evaluate diagnostic reliability; it measures concordance of a diagnosis across assessments conducted at two different time points. As an example, in a meta-analysis of 35 studies, agreement between repeated assessments performed by either the same rater or different raters (ie, "test-retest" reliability) was moderate (kappa = 0.73), although study heterogeneity was high [70]. By contrast, field studies for DSM-5 found only questionable test-retest reliability for the diagnostic criteria for MDD (pooled kappa = 0.28) [71]. Clinician training may improve test-retest reliability [71].

●Stability of diagnosis over time – Patients with a correct initial diagnosis of MDD can later develop symptoms that change their diagnosis. If the diagnosis changes, it most often converts to bipolar disorder or schizophrenia spectrum disorder.

•Bipolar disorder – Approximately 8 to 23 percent of patients who are initially diagnosed with MDD later receive a diagnosis of bipolar disorder, depending on the length of follow-up [72-74]. As an example, in a meta-analysis of over 3000 adolescents and adults diagnosed with MDD and followed longitudinally for over 12 years, 23 percent were diagnosed with bipolar disorder [75]. The probability of switching diagnoses was greatest in the first five years after MDD diagnosis. Studies with shorter lengths of follow-up typically show lower rates of conversion from MDD to bipolar disorder.

Depressive episodes that occur as part of MDD are indistinguishable from those that are part of bipolar disorder; consequently, the assessment of individuals with suspected depression should include questions about symptoms of mania or hypomania (see "Approach to the adult patient with suspected depression", section on 'Assess for additional psychiatric symptoms'). Patient characteristics that are associated with diagnostic conversion to bipolar disorder appear in a table (table 9) [72,76]. Although most individuals with MDD who have these characteristics will not develop bipolar disorder, their presence should raise the index of suspicion for bipolar disorder, especially in the setting of symptoms of hypomania or mania [73]. Additional information about distinguishing MDD and bipolar depression, which differ in treatment, is discussed separately. (See "Bipolar disorder in adults: Assessment and diagnosis", section on 'Unipolar major depression'.)

•Schizophrenia – Some studies estimate that between 5 and 30 percent of those initially diagnosed with MDD will develop a diagnosis of schizophrenia [77-82]. However, most studies come from inpatient psychiatric settings, so rates are likely lower in nonpsychiatric and/or outpatient settings.

●Across cultures – DSM criteria for major depression appear to perform similarly across different languages, ethnicities, and cultures. As an example, a study of over 7000 participants with recurrent depression in China, the Netherlands, the United Kingdom, and the United States suggested that DSM-IV diagnostic criteria for MDD measured the same underlying construct within different patient samples [83].

●Patients with general medical illness – When diagnosing patients with chronic medical illness, we often focus on the mood and cognitive symptoms of depression to make a diagnosis of MDD and rely less on somatic symptoms that could be caused by the patient's general medical conditions [84,85]. Mood and cognitive symptoms include dysphoria, anhedonia, worthlessness or excessive guilt, impaired concentration and decision-making, and suicidal ideation and behavior. This diagnostic approach has demonstrated good agreement with the standard approach of using all DSM-5 criteria [86,87].

Role of the Patient Health Questionnaire — The self-report nine-item Patient Health Questionnaire (PHQ-9) can facilitate the diagnostic process by establishing the number and frequency of depressive symptoms and setting the stage for more in-depth questioning. However, its accuracy as a diagnostic instrument is imperfect. At a cut point of 10 or higher, the PHQ-9 has a sensitivity and specificity of 85 percent for MDD. (See "Screening for depression in adults", section on 'Patient Health Questionnaire-9'.)

Diagnostic instruments — Structured and semistructured, interviewer-administered diagnostic instruments, such as the Structured Clinical Interview for DSM-5, can enable clinicians to clarify ambiguous patient responses and differentiate MDD from bipolar disorder [88]. However, they are labor intensive and generally reserved for specialized treatment or research settings.

Differential diagnosis — Individuals with depressive symptoms who do not meet diagnostic criteria for MDD may have an alternative depressive disorder or a range of other psychiatric or general medical conditions (table 5). Other depressive disorders are discussed below (see 'Other depressive disorders and subtypes' below). Additional information regarding the differential diagnosis of individuals with suspected depression is discussed separately. (See "Approach to the adult patient with suspected depression", section on 'Further assessment and differential diagnosis'.)

Other depressive disorders and subtypes — Individuals with depression can have distinctive patterns of symptoms that are important to recognize because they may inform prognosis or guide treatment. When such patients do not meet criteria for MDD, the DSM-5-TR classifies these symptom patterns as alternative depressive disorders, such as persistent depressive disorder or premenstrual dysphoric disorder (PMDD) (table 5) [3].

By contrast, when such patients meet diagnostic criteria for MDD or persistent depressive disorder, their distinctive patterns of symptoms are classified as "subtypes" by the DSM-5-TR (table 3) [1,3,89]. During a single depressive episode, a patient may have features of more than one subtype or none of them [90]. Although some depressive subtypes do not appear to predict treatment outcomes or differential responses to specific treatment modalities [90,91], others have distinct management strategies (eg, peripartum, psychotic, seasonal subtypes). (See "Mild to moderate postpartum unipolar major depression: Treatment" and "Severe postpartum unipolar major depression: Choosing treatment" and "Unipolar major depression with psychotic features: Acute treatment" and "Seasonal affective disorder: Treatment".)

From a practical perspective, both depressive disorders and subtypes can be differentiated by their time course, duration or number of symptoms, temporal patterns or events, and specific symptom manifestations. In diagnosing MDD or other depressive disorders and their subtypes, clinicians may find it useful to identify these conditions according to these distinguishing features.

Duration and number of symptoms

●Persistent depressive disorder (dysphoria) – Persistent depressive disorder differs from MDD with respect to symptom duration and severity. Persistent depressive disorder manifests with three or more of the following symptoms for at least two consecutive years; at least one symptom must be depressed mood (table 10) [3]:

•Depressed mood most of the day, more days than not

•Decreased or increased appetite

•Insomnia or hypersomnia

•Low energy or fatigue

•Low self-esteem

•Impaired concentration or decision-making

•Hopelessness

Symptom-free periods can occur but may not exceed two consecutive months.

Persistent depressive disorder causes significant distress, and its impact on social and occupational functioning can exceed that of major depression [3].

●Other specified depressive disorder – Other specified depressive disorder applies to patients with depressive symptoms that cause significant distress or impair psychosocial functioning but do not meet the full criteria for a specific depressive disorder [3]. Other specified depressive disorder includes mood disorders in which the number or duration of depressive symptoms does not meet DSM-5-TR diagnostic criteria for MDD. This diagnostic category includes the syndrome previously known as minor depression (table 11) [3]. (See "Minor depression in adults: Epidemiology, clinical presentation, and diagnosis" and "Minor depression in adults: Management".)

●Adjustment disorder with depressed mood – Adjustment disorder with depressed mood is diagnosed when a patient's symptoms of dysphoria occur in the context of psychosocial stressors and do not meet criteria for another specific disorder (eg, major depression or persistent depressive disorder).

Adjustment disorder with depressed mood is marked by low mood, tearfulness, or feelings of hopelessness that occur in response to an identifiable psychosocial stressor (eg, marital conflicts; job loss; academic failure; or persistent, painful illness with progressive disability) and resolve within six months of the stressor [3]. The stressors may be single or multiple and may be recurrent or continuous. The symptoms cause impaired social or occupational functioning or significant distress that exceeds that expected from the stressor.

Although adjustment disorder with depressed mood shares many features of depressive disorders, the DSM-5-TR classifies it as a trauma- and stressor-related disorder.

Temporal pattern or context — These are depressive conditions that occur with a specific temporal pattern or context (eg, seasonal changes, menses, or pregnancy).

●Premenstrual dysphoric disorder – PMDD is a depressive disorder that is differentiated from MDD by its temporal pattern of symptoms. Symptoms occur cyclically during the week before onset of menses and remit with onset of menses or a few days thereafter. PMDD includes emotional (mood swings, irritability, anger, anxiety, feeling overwhelmed, or diminished interest in usual activities) and physical symptoms (breast tenderness, bloating, fatigue, food cravings, and insomnia or hypersomnia). Symptoms cause significant distress or impair usual social or occupational activities. (See "Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder".)

●Peripartum subtype – Peripartum depression refers to a subtype of MDD or persistent depressive disorder that begins during pregnancy or within four weeks of childbirth [1,3,89]. This condition is discussed separately. (See "Unipolar major depression during pregnancy: Epidemiology, clinical features, assessment, and diagnosis" and "Postpartum unipolar major depression: Epidemiology, clinical features, assessment, and diagnosis".)

●Seasonal subtype – Seasonal affective disorder is a depression subtype characterized by recurrent mood episodes that regularly begin during a particular season (eg, winter) and remit during another season (eg, summer) and have occurred for the past two years [1,3,89]. The lifetime number of seasonal episodes substantially outnumbers the nonseasonal episodes. Additional information about MDD with seasonal pattern is discussed separately. (See "Seasonal affective disorder: Epidemiology, clinical features, assessment, and diagnosis" and "Seasonal affective disorder: Treatment".)

"Secondary" depressive disorders — Diagnosis of these disorders involves determining whether the medical condition, medication, or substance is the primary underlying cause of the depressive disorder or simply occurs along with the depressive disorder. This determination requires clinical judgment that considers the timing of the patient's depressed mood relative to the onset of the medical condition or medication. Clinicians should also take into account the patient's prior history of depression, if any, and the response of the depressive symptoms to withdrawing the medication or treating the medical condition.

●Depressive disorder due to another medical condition – Depressive disorder due to another medical condition is characterized by depressed or irritable mood or diminished interest or pleasure in most activities that occurs in conjunction with the onset of another medical condition [3]. Like major depression, its symptoms are persistent, cause significant distress, and impair psychosocial functioning. It differs from MDD in that the history, physical examination, or laboratory studies indicate an underlying medical illness (eg, adrenal insufficiency, Huntington disease, hypercortisolism, hypothyroidism, mononucleosis, multiple sclerosis, obstructive sleep apnea, Parkinson disease, stroke, systemic lupus erythematosus, traumatic brain injury, or vitamin B12 insufficiency) (table 12). (See "Unipolar depression: Pathogenesis", section on 'Secondary depression'.)

In depressive disorder due to another medical condition, mood symptoms predominate; this differentiates it from a general medical illness that causes depressive symptoms such as fatigue, decreased concentration, or sleep disturbance. The depressive symptoms typically begin during the first month of onset of the other medical condition or represent a prodrome of the medical condition [92]. By contrast, when the depressive symptoms clearly precede the onset of the medical condition, the clinician should suspect an alternative diagnosis.

While clinicians should always explore the possibility that another medical illness is causing or contributing to the patient's depression, they should have a particularly high index of suspicion in the following circumstances:

•Severe new-onset depression, including depression with psychotic features

•New-onset depression in an older adult

•New-onset depression in a younger adult with significant chronic or acute medical conditions

•New-onset or recurrent depression that is not readily understood in the context of the patient's psychosocial stressors and circumstances

•Depression that has not responded to treatment attempts

•Depression with significant neurocognitive impairment

The evaluation for general medical illnesses in patients with depressive symptoms is discussed separately. (See "Approach to the adult patient with suspected depression", section on 'Evaluate for general medical illness'.)

●Substance- or medication-induced depressive disorder – Substance/medication-induced depressive disorder is characterized by depressed or irritable mood or diminished interest or pleasure in most activities that develops in the context of using prescribed medications or recreational drugs that can cause mood disturbance (table 12) [3]. The mood disturbance causes significant distress or impairs psychosocial functioning. This mood disorder can be caused by intoxication or withdrawal from alcohol and a wide range of drugs, including cannabis, amphetamines, cocaine, and other stimulants [93]. Common prescription medications associated with this disorder include glucocorticoids, beta blockers, and beta interferon. (See "Unipolar depression: Pathogenesis", section on 'Drugs of abuse' and "Unipolar depression: Pathogenesis", section on 'Medications'.)

Substance/medication-induced depressive disorder is not diagnosed when:

•The patient has a history of recurrent depressive episodes.

•The mood disturbance precedes onset of medication exposure or drug intoxication or withdrawal.

•The mood disturbance persists for over one month after medication or drug discontinuation and/or cessation of withdrawal.

•The mood disturbance occurs solely during an episode of delirium. (See "Diagnosis of delirium and confusional states".)

Specific symptom constellations

●Anxious subtype – Depressive disorders with high levels of anxiety symptoms are referred to as "anxious depression" (table 3) [94]. Approximately 40 to 50 percent of major depressive episodes qualify as anxious depression [1,90,95]. Anxiety symptoms can include worrying, fear, muscle tension, restlessness, rumination, health anxieties, and panic attacks. On examination, patients may exhibit psychomotor agitation (eg, pacing and hand-wringing). Anxiety may be a prodromal or residual feature of depressive episodes [96]. Genetic, neuroimaging, and electroencephalography studies suggest that the neurobiology of anxious depression may differ from that of nonanxious depression [97,98].

Anxiety symptoms that are part of a depressive syndrome may be difficult to distinguish from anxiety disorders that are comorbid with depressive disorders; the latter are discussed separately. (See "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis".)

Individuals with MDD and anxious features may have a worse prognosis, compared with patients who have other depression subtypes [90,95,99,100]. The treatment of adults with MDD and anxiety symptoms is discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Addressing specific symptoms'.)

●Atypical subtype – Atypical depression is characterized by mood reactivity (eg, feeling better in response to positive events), oversleeping, and overeating [1,3,89,101]. The latter is in contrast to the "typical" depressive symptoms of insomnia and anorexia (table 3) [1,3,89,101].

Atypical depression may account for 15 to 50 percent of depressive episodes [89,90,102-104] and may be associated with hypocortisolemia [89] and a history of trauma [105]. Compared with other types of depression, atypical depression is associated with female gender, earlier age of onset, family history of depression, higher rates of comorbidity (eg, anxiety disorders, substance use disorders, personality disorders, and obesity), more depressive symptoms, greater functional impairment, and more suicide attempts [1,101,106].

It is unclear whether atypical depression requires a distinct approach to management [90,95,103,104]. However, a patient's specific symptoms can influence the selection of a specific antidepressant. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Tailoring antidepressant selection'.)

●Catatonic subtype – Catatonic features are characterized by prominent psychomotor disturbances that occur during most of the depressive episode (table 3). These can range from marked psychomotor retardation with immobility, mutism, or stupor to agitation with excessive, purposeless limb movements, restlessness, and combativeness. (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis".)

Individuals with catatonic features generally require urgent management. (See "Catatonia: Treatment and prognosis".)

●Melancholic subtype – Distinctive features of the melancholic subtype include disturbed affect that does not respond to improved circumstances, diurnal variations (eg, mood and energy worse in the morning), and high rates of neurovegetative symptoms (table 3) [1,3,89,107]. Melancholic features are present in approximately 15 to 30 percent of major depressive episodes [90,104,108,109]. Patients with melancholic features may have higher rates of neurocognitive dysfunction and severe illness and may require different management [1,3,109,110].

Putative biologic correlates of melancholic features include hypercortisolemia and disturbances in sleep architecture [1,89,107].

●Mixed subtype – Individuals with this subtype meet full criteria for a depressive episode, such as MDD (table 6) or persistent depressive disorder (table 10), and also have some symptoms of mania or hypomania (table 3) [3]. Some studies have also included irritable mood and psychomotor agitation as symptoms of mixed features [111,112].

Approximately 25 to 40 percent of individuals with major depression also have subthreshold hypomania [111,113-115]. Prospective observational studies have found that among individuals with major depression (n = 488 and 573), subthreshold hypomania was present in approximately 25 to 40 percent [111,115]. Compared with patients with MDD without mixed features, those with mixed features are more likely to have psychiatric comorbidities (eg, panic disorder and substance use disorders) or a family history of mania and to convert to bipolar disorder (ie, experience an episode of mania or hypomania) [111]. They may also respond less well to standard antidepressant treatment.

Individuals who meet full criteria for hypomania (table 8) or mania (table 7) are diagnosed with bipolar disorder rather than MDD with mixed features [3,116]. (See "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)

●Psychotic subtype – Psychotic symptoms include delusions (false, fixed beliefs) and hallucinations (false sensory perceptions). Psychotic symptoms can occur at any time during an episode of MDD or persistent depressive disorder [1,3,89]. Delusions and hallucinations can be subtle and are often "mood congruent," meaning that they involve themes of excessive guilt, punishment, impending disaster, or hopelessness. They are important to identify because patients with psychotic features due to depression or another cause require expedited evaluation and treatment. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Depression in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Depression in adults (Beyond the Basics)" and "Patient education: Depression in children and adolescents (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Meanings of depression – Depression can refer to a mood state, syndrome, or specific mental disorder (table 1). (See 'Definitions of depression' above.)

●Symptoms of depression – Major depression causes symptoms that are heterogeneous and impair function across emotional, physical, and cognitive domains. Common depressive symptoms include depressed mood, loss of interest or pleasure, sleep and appetite disturbances, fatigue, cognitive dysfunction, psychomotor agitation or retardation, feelings of worthlessness or guilt, and suicidal ideation and behavior (table 2). (See 'Clinical features' above.)

●Impact on function – Major depression causes disability, impacts functioning and quality of life, and can adversely affect the prognosis of general medical illnesses. (See 'Impact on function' above.)

●Psychiatric comorbidities – Many individuals with major depression suffer from comorbid psychiatric disorders. The most common of these include anxiety disorders (eg, generalized anxiety disorder, panic disorder, social anxiety disorder), alcohol and other substance use disorders, posttraumatic stress disorder, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and personality disorders. (See 'Psychiatric' above.)

●Medical comorbidities – Depression and comorbid general medical illnesses often occur together. Major depression increases the risk of developing general medical conditions and can have a negative impact on their outcomes. Conversely, medical illnesses increase the risk of depression and can worsen its prognosis. (See 'Medical illnesses' above.)

●Diagnosis

•Major depressive disorder (MDD) – The diagnosis of MDD is established with a clinical interview to determine if the patient meets specific diagnostic criteria (table 6). (See 'Diagnostic criteria' above.)

•Other depressive disorders and subtypes – Individuals with depression can have distinctive patterns of symptoms that are important to recognize because they may inform prognosis or guide treatment. These include depressive disorders other than MDD and subtypes of MDD (table 10 and table 11). Clinicians can differentiate the depressive disorders and subtypes by their time course, duration or number of symptoms, precipitating factors, and specific symptom manifestations (table 5 and table 3). (See 'Other depressive disorders and subtypes' above.)

•Differential diagnosis – The differential diagnosis of depressive disorders is discussed separately (table 5). (See "Approach to the adult patient with suspected depression", section on 'Patients without prominent depressive symptoms'.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Jeffrey M Lyness, MD, who contributed to earlier versions of this topic review.