Overview of depression

Article written and reviewed by Dr Luca Moretti

The term depression derives from the Latin deprimere, meaning to press down, and in everyday language is often used as a synonym for sadness or discouragement. In medicine, however, the term must be used more precisely: it can refer to a depressive symptom, a depressive episode or, more broadly, one of several depressive disorders. These levels are not equivalent. Depressed mood is a symptom, a depressive episode is a clinical configuration defined by the simultaneous presence of multiple symptoms for a sufficiently prolonged period, while the disorder is the nosological entity also defined by course, recurrence of episodes and exclusion of alternative conditions.

Clinically significant depression therefore does not coincide with a normal negative emotional reaction. A depressive episode typically includes depressed, irritable or empty mood or a marked loss of interest or pleasure, associated in varying combinations with cognitive, motivational, psychomotor and somatic changes. Reduced energy, difficulty concentrating and making decisions, feelings of guilt or self devaluation, pessimism, changes in sleep and appetite, psychomotor slowing or agitation and thoughts of death or suicide may occur. For a depressive episode to be diagnosed, the presentation must have a duration, intensity and pervasiveness consistent with diagnostic definitions and cause clinically significant distress or functional impairment.

The distinction from physiological sadness does not depend solely on the presence of a negative event. A person may be profoundly sad after bereavement, separation, illness or loss without meeting criteria for a depressive disorder; at the same time, a stressful event does not exclude the possibility of a true depressive episode developing. Assessment considers the overall symptoms, their persistence, the capacity to experience positive emotions, the presence of anhedonia, self devaluation, hopelessness, neurovegetative changes, functional impairment and suicide risk. In DSM-5-TR, bereavement itself is not an exclusion criterion for a major depressive episode, while prolonged grief disorder is a separate diagnosis when its clinical requirements are met.

From an epidemiological perspective, depression is one of the most important mental health problems worldwide. In 2025, the World Health Organization estimated that approximately 5.7% of adults have a depressive disorder, with a prevalence of 4.6% in men and 6.9% in women, amounting to approximately 332 million people worldwide. Estimated prevalence among adults aged 70 years or older is 5.9%, and depression is overall about one and a half times more common in women than in men. The disorder can nevertheless occur at any stage of life, from childhood to older age, and has partly different characteristics depending on age, biological context and social conditions.

The impact of depression is not limited to emotional suffering. Clinically relevant presentations can impair self care, intimate relationships, family life, education, ability to work and social participation. Cognitive impairment, loss of initiative, fatigue and anhedonia can drastically reduce the ability to perform daily activities even when the person appears physically intact from the outside. Depression is also frequently associated with somatic diseases and other psychiatric disorders, with often bidirectional relationships that can worsen the course of both conditions.

An essential aspect of clinical assessment is distinguishing episodes from the disorders in which they occur. A major depressive episode is not, by itself, synonymous with major depressive disorder: it is a clinical episode that may occur in major depressive disorder but also in bipolar disorders. In bipolar I disorder, diagnosis requires at least one manic episode, and major depressive episodes may occur but are not required for diagnosis. Bipolar II disorder instead requires at least one hypomanic episode and at least one major depressive episode, with no history of a manic episode. Correctly reconstructing any episodes of mania or hypomania is therefore essential before classifying depression as unipolar.

Different patterns of course also exist within depressive disorders. International classifications do not organize every diagnosis in the same way: DSM-5-TR and ICD-11 use partly different categories, specifiers and terminology. In general, clinical history makes it possible to distinguish presentations characterized by a single episode, recurrent forms with multiple episodes separated over time and forms with persistent depressive symptoms. This distinction is not merely terminological, because episode frequency, duration of residual symptoms, severity, comorbidity and treatment response help define prognosis and therapeutic strategy.

The etiology of depression is multifactorial. There is no single cause capable of explaining all cases, and it is scientifically incorrect to attribute the disorder to a single neurochemical deficit. Individual vulnerability arises from interactions among genetic, neurobiological, psychological and environmental factors. Early adverse events, trauma, major losses, chronic stress, social isolation and socioeconomic hardship may increase risk in vulnerable individuals, but do not inevitably cause a depressive disorder. Likewise, the presence of a familial or genetic predisposition modifies risk without constituting an inevitable destiny.

The relationship between depression and physical health is particularly complex. Cardiovascular, metabolic, oncological, neurological and other chronic diseases may be more frequently associated with depressive symptoms and disorders, while depression may in turn interfere with treatment adherence, physical activity, nutrition, sleep and management of somatic disease. Psychoactive substances, alcohol, some medications and specific medical conditions can also produce or worsen depressive symptoms. Diagnosis should therefore not be made by isolating psychiatric symptoms from the rest of the clinical history.

At the pathophysiological level, studies have documented alterations in numerous systems, but none currently constitutes a necessary and sufficient mechanism or a diagnostic biomarker usable in clinical practice. Involved processes include monoaminergic systems, glutamatergic neurotransmission, synaptic plasticity, neurotrophic factors, regulation of the hypothalamic pituitary adrenal axis, circadian rhythms, energy metabolism, immune and inflammatory processes, and brain networks responsible for mood regulation, reward, salience and cognitive control. The observed alterations are not uniform across all patients and contribute to the biological heterogeneity of the disorder.

The older model according to which depression simply results from a deficiency of serotonin or other monoamines is therefore inadequate. Monoaminergic neurotransmission remains relevant to pathophysiology and to the mechanism of action of many antidepressants, but contemporary evidence indicates a much more complex network of interactions. Prolonged stress, alterations in synaptic plasticity, changes in corticolimbic circuits and reward systems, neuroendocrine dysregulation and, in some patients, increased inflammatory signals are among the most extensively studied processes. These mechanisms are useful for understanding the disorder and developing new therapies, but they still do not allow depression to be diagnosed with a single biological test.

The clinical presentation is extremely heterogeneous. In some people, sadness, anhedonia and slowing predominate; in others, irritability, anxiety, agitation, insomnia or somatic symptoms are more prominent. Difficulties with memory and concentration, reduced libido, changes in appetite and weight, alterations in the sleep wake rhythm and a marked reduction in motivation may occur. Severe forms may include psychotic symptoms, severe impairment of food and fluid intake or high suicide risk. Irritability may be particularly evident in children and adolescents, whereas cognitive and somatic manifestations in older adults may make recognition of the condition more complex.

Depression is also frequently accompanied by comorbidities. Anxiety disorders, problematic alcohol or other substance use, personality disorders, sleep disorders and chronic medical conditions can alter symptoms, suicide risk, treatment response and prognosis. Significant anxiety does not exclude depression and, conversely, depressive symptoms should not lead clinicians to overlook the possibility of a primary anxiety disorder, bipolar disorder, a substance use disorder or a medical condition responsible for the presentation.

Diagnosis is clinical. There are currently no blood tests, brain imaging examinations or other instrumental tests capable of independently confirming a depressive disorder. Assessment begins with the medical history and clinical interview and reconstructs current symptoms, duration, temporal course, level of functioning, previous depressive episodes, any periods of mania or hypomania, previous treatments, substance use, medications, comorbid diseases, psychiatric family history and psychosocial context. Mental status examination allows assessment of affect, thought, behavior, psychomotor activity, guilt or hopelessness, possible psychotic symptoms and judgment.

Validated questionnaires and scales can be useful for screening, quantifying symptom severity and especially monitoring change over time, but they do not replace clinical diagnosis. Similarly, laboratory or instrumental investigations are selected on the basis of the history and physical examination when it is necessary to investigate medical conditions that may mimic or worsen a depressive syndrome; there is no universal panel of tests capable of demonstrating the presence of depression.

Assessment of suicide risk is an essential component of evaluation. Thoughts of death and suicidal ideation may occur during a depressive episode, especially in more severe presentations, but suicide is a multifactorial phenomenon and cannot be attributed exclusively to depression. Clinical assessment considers ideation, intent, any planning, previous attempts, access to potentially lethal means, precipitating factors, social support and protective factors. Acute risk, severe psychotic symptoms, catatonia, inability to eat or drink, or severe compromise of safety requires prompt specialist management.

Treatment depends on the correct diagnosis, severity, characteristics of the episode, clinical history, comorbidities, treatments already attempted, the person's preferences and availability of interventions. In adult unipolar depression, strategies with established efficacy include psychotherapy, antidepressant pharmacotherapy and, when appropriate, their combination. Modern guidelines favor a shared and individualized approach: psychological and behavioral options are often initially considered for less severe forms, whereas antidepressants have a greater role in more severe forms or when the person prefers them, has previously benefited from them or has clinical characteristics supporting their use.

Psychotherapies with evidence of efficacy include cognitive behavioral therapy, behavioral activation, interpersonal psychotherapy and problem solving therapy. No psychotherapy is universally superior for every patient, and selection also depends on clinical characteristics, accessibility, preferences and previous response. Pharmacotherapy includes different classes of antidepressants; selective serotonin reuptake inhibitors are frequently used as initial options because of their overall balance of efficacy, tolerability and safety, but drug selection should consider symptom profile, comorbidities, interactions, adverse effects and previous responses.

Treatment response should not be assessed solely as a partial reduction in symptoms. The clinical goal is, whenever possible, to achieve remission, restore functioning and reduce the risk of relapse or recurrence. After remission, treatment is generally continued for an appropriate period, and longer maintenance therapy may be indicated in people at high risk of further episodes. Persistent residual symptoms, multiple episodes, high severity, comorbidity and incomplete response to previous treatments are among factors that can increase recurrence risk.

When depression is severe, resistant or requires a particularly rapid response, somatic and neuromodulation treatments may be used. Electroconvulsive therapy is a contemporary medical treatment performed under general anesthesia, with established indications especially in severe depression when a rapid response is needed, when other treatments have not produced sufficient benefit or when the person chooses it after adequate information. Repetitive transcranial magnetic stimulation is a noninvasive option for selected patients, while ketamine and esketamine have introduced rapid acting pharmacological strategies for specific forms of treatment resistant depression, with indications, administration methods and availability depending on the regulatory and clinical context.

Vagus nerve stimulation is an invasive procedure intended for a highly selected population with chronic or recurrent treatment resistant depression; regulatory indications, reimbursement and availability vary among health systems. It is therefore not a routine therapy for common depression, but a possible specialist strategy in highly treatment resistant presentations.

Interventions such as music therapy and animal assisted interventions may provide benefits for depressive symptoms and psychological wellbeing in some settings, but heterogeneity in studies and intervention methods requires caution when interpreting results. They may be used as complementary interventions within selected programs, but should not replace psychotherapy, pharmacotherapy or somatic treatments when these are clinically indicated.

Prognosis is variable. Many depressive episodes improve or remit with appropriate treatment, but some patients experience relapses, new episodes, persistent residual symptoms or a chronic course. Depression should therefore be interpreted neither as an inevitably permanent condition nor as a problem that will always resolve spontaneously. Correct diagnosis, distinction between unipolar and bipolar depression, appropriate treatment of the acute phase, prevention of recurrence and monitoring of suicide risk are fundamental to improving long term outcome.

In summary, depression comprises a heterogeneous set of clinical phenomena ranging from a single symptom to a depressive episode and to depressive disorders themselves. Correct assessment therefore requires considering symptoms, duration, severity, functioning and course together, avoiding both the medicalization of every normal experience of sadness and the underestimation of pathological conditions that can cause major disability and risk to life. Diagnostic classifications, guidelines and contemporary research converge on the need for comprehensive clinical assessment and individualized treatment based on the best available evidence.

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