Major depressive episode

Article written and reviewed by Dr Luca Moretti

A major depressive episode is a psychopathological syndrome defined by the onset, for a sufficiently prolonged period, of a constellation of disturbances in mood, the capacity to experience pleasure, cognitive functions, psychomotor activity, and neurovegetative functions, with clinically significant repercussions on the individual’s functioning. It is essential to distinguish the episode from the disorder in which it occurs: a major depressive episode does not by itself constitute a diagnosis of major depressive disorder, because the same depressive phenotype can also occur during the course of a bipolar disorder. Correct classification therefore requires a longitudinal reconstruction of the entire psychopathological history, not merely observation of the symptoms present at the time of assessment.

In the American Psychiatric Association DSM-5-TR, the diagnostic core of the episode consists of the presence, during the same period of at least two weeks, of five or more of the nine specified symptom domains, with at least one being depressed mood or a marked loss of interest or pleasure. The symptoms must represent a change from the previous level of functioning and cause clinically significant distress or functional impairment. The World Health Organization ICD-11 uses a very similar but not identical construct: it considers ten symptom domains, explicitly including hopelessness, and likewise requires a persistent clinical picture for at least two weeks with at least one of depressed mood or diminished interest or pleasure.

The distinction between episode and disorder is clinically crucial. In major depressive disorder, one or more major depressive episodes may occur in the absence of a history of mania or hypomania pointing toward bipolar disorder. In bipolar I disorder, a major depressive episode may occur in a person who has experienced at least one manic episode, whereas in bipolar II disorder the history includes at least one hypomanic episode and at least one major depressive episode, with no previous manic episodes. The phenomenology of the depressive episode can be very similar in unipolar and bipolar forms, and no single symptom can distinguish them with certainty.

From an epidemiological perspective as well, major depressive episode and major depressive disorder should not automatically be treated as synonymous. Estimates depend on the diagnostic system, the instrument used, the observation period, and the population studied. In the World Mental Health Surveys, conducted using DSM-IV criteria in 18 countries, the mean lifetime prevalence of major depressive episode was 14.6% in high-income countries and 11.1% in low- or middle-income countries, while 12-month prevalence was 5.5% and 5.9%, respectively. These data document both the high frequency of the phenomenon and the considerable geographic and methodological variability of the estimates.

More recent surveillance data confirm that major depressive episode remains extremely common. In the 2024 US National Survey on Drug Use and Health, based on a definition aligned with DSM-5 criteria, approximately 8.2% of adults reported a major depressive episode in the previous year. This figure cannot be transferred directly to the Italian population, but it illustrates the magnitude of the problem in a large contemporary population survey.

The episode can occur at any age, but its phenomenology varies across the lifespan. In children and adolescents, irritability may replace depressed mood as the predominant affective manifestation, whereas in older adults psychomotor slowing, somatic symptoms, and cognitive difficulties may predominate, with possible clinical overlap with neurological diseases or neurocognitive disorders. Pregnancy and the postpartum period are also phases in which it is particularly important to recognize the onset of depressive symptoms promptly and to investigate features suggestive of bipolarity or postpartum psychosis.

The clinical importance of the episode does not depend solely on the number of symptoms. Presentations that formally meet the same diagnostic threshold may differ profoundly in intensity, duration, impairment, suicide risk, presence of psychosis, mixed features, or catatonia. For this reason, categorical diagnosis must be complemented by a dimensional assessment of severity, disability, and patient safety.

Etiology, risk factors, pathogenesis and pathophysiology

There is no single etiological cause capable of explaining all major depressive episodes. The episode is a heterogeneous clinical phenotype that emerges from the interaction of biological vulnerabilities, environmental experiences, and psychological processes, and it may occur within different nosographic entities. This heterogeneity makes it scientifically inadequate to view depression simply as the consequence of a deficiency of serotonin, norepinephrine, or another single neurotransmitter.

In major depressive disorder, a necessary and sufficient cause is generally not identified. Risk is instead distributed across numerous genetic and environmental determinants of small or moderate effect. Large contemporary genomic analyses confirm a highly polygenic architecture: a trans-ancestry study published in 2025, including hundreds of thousands of cases of major depression and millions of controls, identified hundreds of genetic associations distributed across numerous loci. No single variant has sufficient diagnostic or predictive value for an individual patient.

A family history of depressive or bipolar disorders increases risk, but clinical expression depends on the interaction between genetic background and environmental exposures. Genetic vulnerability involves multiple neuronal and synaptic processes and does not follow a simple Mendelian model. The absence of a known family history likewise does not substantially reduce the need to consider a depressive diagnosis when the clinical picture is compatible.

Factors associated with increased risk include early adverse experiences, childhood maltreatment, persistent psychosocial stress, negative life events, social isolation, certain adverse socioeconomic conditions, sleep disorders, chronic pain, and numerous medical illnesses. These associations are probabilistic and should not be interpreted as deterministic causal relationships: many exposed people do not develop depression, and many patients with depression have no single identifiable precipitating factor.

Stressful events may contribute to onset through activation of neuroendocrine and autonomic systems, changes in sleep and circadian regulation, cognitive and behavioral processes, and alterations in reward and threat processing. The relative contribution of these mechanisms varies considerably among individuals and between successive episodes in the same person.

The hypothalamic-pituitary-adrenal axis is one of the most extensively studied systems. Alterations in cortisol regulation and stress-feedback mechanisms have been detected in subgroups of patients, but these findings are not uniformly present and cannot be used as diagnostic tests. Similar neuroendocrine alterations may also occur in other psychiatric or medical conditions.

The immune system has also been extensively studied. In a proportion of patients with major depression, mean increases in peripheral inflammatory markers, including C-reactive protein and certain cytokines, can be observed, but there is substantial overlap with the non-depressed population. Inflammation therefore represents a potentially relevant mechanism for specific subgroups rather than a universal cause or a diagnostic biomarker of depression.

Serotonergic, noradrenergic, and dopaminergic monoaminergic systems participate in the regulation of mood, motivation, reward, arousal, and several cognitive functions. The efficacy of drugs that modulate these systems demonstrates their therapeutic relevance, but it does not imply that the disorder simply results from a global reduction in monoamines. The delay between pharmacological changes in monoaminergic transmission and clinical response suggests the involvement of more complex receptor, transcriptional, synaptic, and circuit-level adaptations.

Increasing attention is being paid to glutamatergic transmission and synaptic plasticity. The rapid antidepressant effects observed with functional NMDA receptor antagonism through ketamine and esketamine have strengthened interest in mechanisms of plasticity and intracellular pathways regulating synapse formation and remodeling. Here too, however, no single glutamatergic defect has been demonstrated in all patients.

Neurotrophins such as BDNF and intracellular pathways involved in neuronal plasticity have been associated with depression and treatment response. Prolonged stress, endocrine alterations, and inflammatory processes may interfere with these systems, but available data describe interacting networks rather than a single pathogenetic sequence.

Structural neuroimaging studies conducted in large samples show very small average differences between groups of patients with major depressive disorder and controls. Among other findings, the ENIGMA consortium has documented a mean reduction in hippocampal volume, particularly in patients with recurrent or early-onset episodes, as well as distributed cortical alterations. These results are valuable for understanding population-level neurobiology but show substantial overlap between groups and do not permit depression to be diagnosed by magnetic resonance imaging.

Functional studies likewise describe average alterations in networks involved in emotional processing, reward, cognitive control, self-referential processing, and salience. The prefrontal cortex, anterior cingulate, amygdala, striatum, hippocampus, and other regions interact within distributed circuits; referring to a single “depression area” is therefore biologically incorrect.

Sleep represents another relevant pathophysiological level. At the group level, patients with depression have been reported to show reduced sleep continuity, changes in deep NREM sleep, earlier onset of REM sleep, and greater REM pressure during the first part of the night. These findings are variable and nonspecific and do not justify routine use of polysomnography for diagnostic purposes.

Circadian alterations may contribute to diurnal mood variation, sleep disturbances, and certain seasonal patterns. Circadian systems interact with melatonin, cortisol, body temperature, sleep, metabolism, and brain reward circuits. Their contribution, however, varies considerably across different depressive phenotypes.

In late-life depression, the bidirectional relationship with cerebrovascular disease is particularly important. White-matter lesions, small-vessel disease, and abnormalities of frontostriatal circuits are more common in some patients with late-onset depression. The concept of vascular depression describes this possible clinical-biological association but does not constitute a universal explanation of depression in older adults.

Medical conditions can contribute to the onset or worsening of depressive symptoms through different mechanisms. Neurological, endocrine, inflammatory, oncological, and systemic diseases may directly alter brain function or may cause pain, disability, sleep disturbance, and psychological stress. When there is evidence that the mood disturbance represents a direct pathophysiological consequence of a medical condition, diagnostic classification should take this into account rather than automatically attributing the presentation to primary major depressive disorder.

Similarly, medications and substances may induce or worsen depressive symptoms. Causal attribution requires a plausible temporal relationship between exposure, dose change, intoxication or withdrawal, and symptom onset, together with assessment of alternative explanations. It is incorrect to regard entire drug classes as definite causes of depression on the basis of inconsistent associations.

From a psychological perspective, negative cognitive biases, rumination, reduced positive reinforcement, avoidance, and loss of rewarding activities may contribute to maintaining symptoms. These mechanisms underpin the rationale for treatments such as cognitive behavioral therapy and behavioral activation, but they do not constitute an exclusive etiological explanation.

The synthesis most consistent with contemporary knowledge is therefore that of a disorder of mood-regulation systems arising from interactions among genetics, environment, stress, learning, neurotransmission, plasticity, endocrine and immune systems, and brain circuits. None of the alterations described is currently necessary or sufficient to identify a major depressive episode in an individual, which is why diagnosis remains clinical.

Clinical manifestations

Clinical assessment begins with the history. The patient may present spontaneously reporting sadness, loss of interest, or inability to experience pleasure, but it is not uncommon for the initial reason for consultation to be insomnia, fatigue, reduced concentration, pain, gastrointestinal symptoms, weight loss, or other somatic complaints. The clinician must therefore actively reconstruct the presence, intensity, duration, and temporal course of affective, cognitive, psychomotor, and neurovegetative symptoms.

Depressed mood may be described as sadness, emptiness, hopelessness, dejection, or inability to imagine future improvement. Some patients do not spontaneously use the term depression and instead report feeling “switched off,” “without energy,” or emotionally numb. In children and adolescents, persistent irritability may be the predominant affective manifestation.

The other cardinal symptom is a marked decrease in interest or pleasure. Anhedonia may affect hobbies, social relationships, sexuality, work, eating, or activities that were previously rewarding. It must be distinguished from a simple reduction in opportunities to engage in certain activities: what is clinically significant is the loss of motivation or the ability to derive pleasure from them compared with usual functioning.

The patient may progressively withdraw from relationships, abandon personal and family activities, and reduce participation in school or work. Reduced initiative may be mistakenly interpreted by others as laziness or voluntary disinterest, whereas in more severe presentations it reflects profound motivational and psychomotor impairment.

Changes in appetite may occur in either direction. More commonly, the patient reports little interest in food, reduced intake, and weight loss, but some phenotypes are characterized by increased appetite, hyperphagia, or weight gain. In children, nutritional impairment may also present as failure to achieve the expected weight gain.

Sleep disturbances include insomnia and hypersomnia. Insomnia may be initial, when difficulty falling asleep predominates; middle, when sleep is fragmented by frequent or prolonged awakenings; or terminal, when the patient awakens early and cannot return to sleep. Hypersomnia may consist of prolonged nocturnal sleep, daytime naps, or marked difficulty maintaining wakefulness.

The number of hours slept alone does not define the symptom. It is important to assess the change from the usual pattern, sleep quality, possible sleep-disordered breathing, restless legs syndrome, shift work, substances, medications, and other conditions that may explain the disturbance.

Changes in psychomotor activity have particular clinical value when they are also observable by others. Retardation may manifest as reduced facial expression, immobile posture, slow speech, increased response latency, fewer spontaneous movements, and difficulty initiating activities. Agitation may instead cause restlessness, inability to remain seated, continuous manipulation of the hands or clothing, and repetitive pacing.

Fatigue and loss of energy can be profound. Daily activities that were previously automatic, such as getting out of bed, washing, dressing, cooking, or going to work, may require disproportionate effort. In severe cases, the patient may spend much of the day immobile or in bed.

Feelings of worthlessness, self-devaluation, or pathological guilt must be distinguished from normal self-criticism. The patient may feel disproportionately responsible for family, financial, or occupational problems, retrospectively reinterpret neutral events as evidence of personal inadequacy, or become convinced of being an unbearable burden to others.

In more severe forms, guilt may reach delusional intensity. The patient may be unshakably convinced of having committed nonexistent offenses, caused catastrophes, or deserved punishment. The presence of delusions or hallucinations changes severity and the therapeutic approach and must be specifically investigated.

Cognitive impairment includes difficulty with concentration, reduced attention, indecisiveness, slowed thinking, and subjective memory complaints. The patient may take a long time to make simple decisions, lose the thread of a conversation, or be unable to read, work, or follow television programs as before.

In older adults, cognitive impairment may be particularly marked and overlap with a neurocognitive disorder. The presence of depression does not allow one to conclude automatically that the deficit is reversible, nor does it exclude concomitant neurodegenerative disease. Longitudinal evolution and, when indicated, neuropsychological and neurological assessment are essential.

Thoughts of death span a spectrum from believing that it would be preferable not to wake up to active suicidal ideation with intent, planning, and preparation. Assessment must directly explore the presence of suicidal thoughts, their frequency, duration, and controllability, intent to act, any plans, access to means, preparatory behaviors, previous attempts, and protective factors.

It is not scientifically appropriate to infer future risk from a single element such as the presence or absence of a plan. A specific plan, immediate access to lethal means, previous attempts, agitation, substance use, hopelessness, psychotic symptoms, and recent clinical changes may increase concern, but suicide cannot be predicted with certainty using a scale or a simple sum of risk factors.

Some patients have marked anxiety, tension, rumination, irritability, or fear that something terrible may happen. Anxiety may represent a specifier of the depressive presentation, a dimensional feature, or a comorbid anxiety disorder. The two conditions may coexist and should not be regarded as mutually exclusive.

Somatic symptoms are common and may include headache, diffuse pain, gastrointestinal disturbances, a feeling of bodily heaviness, reduced libido, and many other manifestations. Their presence does not distinguish “psychological” depression from a medical condition and should not preclude an organic evaluation when the history and physical examination make it appropriate.

In presentations with melancholic features, profound anhedonia, lack of reactivity to positive events, morning worsening, early awakening, psychomotor changes, loss of appetite or weight, and intense guilt may predominate. The melancholic phenotype is not synonymous with severity alone, because it is defined by a specific constellation of clinical features.

In presentations with atypical features, mood retains some reactivity to positive events, and hypersomnia, increased appetite or weight, a sensation of heaviness in the limbs, and persistent interpersonal rejection sensitivity may occur. The term “atypical” is historical and does not imply that these manifestations are exceptional.

When manic or hypomanic symptoms occur concurrently with depression, mixed features should be investigated and, above all, the possibility of bipolar disorder must be reassessed. Elevated or expansive mood, grandiosity, increased talkativeness, flight of ideas, increased energy or goal-directed activity, decreased need for sleep, and high-risk behaviors are particularly relevant.

Psychosis during a depressive episode may manifest with delusions or hallucinations. Their content may be mood-congruent, such as guilt, ruin, illness, nihilism, or deserved punishment, or mood-incongruent. It is essential to establish the temporal relationship between psychosis and mood disturbance because psychotic symptoms that persist outside affective episodes profoundly alter the differential diagnosis.

Catatonia is a distinct psychomotor syndrome that may accompany mood disorders, psychotic disorders, and numerous medical conditions. Stupor, mutism, negativism, posturing, catalepsy, waxy flexibility, stereotypy, mannerisms, agitation not influenced by external stimuli, grimacing, echolalia, and echopraxia should prompt a specific assessment because catatonia may be associated with severe medical complications and require urgent treatment.

The episode may begin rapidly over a few days or develop more gradually over several weeks. Sleep disturbances, anxiety, irritability, loss of energy, concentration difficulties, and progressive withdrawal from activities may precede it. Reconstructing the timeline helps distinguish the true onset of the episode from prodromal symptoms and identify possible precipitating factors.

During the mental status examination, the clinician evaluates appearance, behavior, contact, cooperation, psychomotor activity, speech, subjective mood, observed affect, thought process and content, perception, cognitive functions, insight, and judgment. None of these findings is individually pathognomonic, but together they contribute to assessment of severity and differential diagnosis.

Functional impairment should be examined concretely by asking what has changed in study, work, household management, relationships, and self-care. Some people apparently maintain a high level of functioning through exceptional effort; in others, impairment is immediately evident and may progress to complete inability to provide for nutrition, hygiene, or everyday needs.

The entire clinical assessment must finally be placed within the longitudinal history. The number and duration of previous episodes, interepisode recovery, any periods of pathologically increased energy and activity, seasonality, relationship with pregnancy or the postpartum period, response to previous treatments, and family history of depression, bipolarity, and suicide are essential information for correctly interpreting the current presentation.

Assessment and diagnosis

The diagnosis of a major depressive episode is essentially clinical. There is currently no blood, genetic, neuroendocrine, electrophysiological, or neuroimaging test with sufficient sensitivity and specificity to confirm or exclude the episode in an individual patient. The diagnostic process must therefore begin with an in-depth interview and proceed according to a rational sequence that first establishes the presence of the depressive syndrome and then identifies the disorder in which it occurs.

The first level consists of systematically reconstructing the symptoms present over the previous weeks. It is necessary to establish when symptoms began, whether they are present every day or nearly every day, how long they last during the day, whether they represent a change from usual functioning, and what impact they have on personal, social, academic, or occupational life.

According to the DSM-5-TR, specific clinical conditions must be met to identify a major depressive episode. The following nine domains are presented in paraphrased form to preserve their diagnostic meaning without inappropriately conflating DSM and ICD terminology.

To meet the DSM-5-TR symptom threshold, at least five of the following nine domains must be present during the same period of at least two weeks; at least one must be depressed mood or loss of interest or pleasure.

• Depressed mood for most of the day, nearly every day; in children and adolescents it may manifest predominantly as irritability.
• Marked loss of interest or pleasure in all or almost all activities, present for most of the day and nearly every day.
• Weight or appetite significantly changed from usual, either increased or decreased; in children, failure to achieve expected weight gain may be relevant.
• Insomnia or hypersomnia present nearly every day.
• Psychomotor agitation or retardation nearly every day and observable by others, not limited to a subjective sensation.
• Fatigue or loss of energy nearly every day.
• Worthlessness or pathological guilt, excessive or inappropriate, which in severe cases may reach delusional intensity.
• Cognitive difficulties consisting of reduced ability to think or concentrate or marked indecisiveness, nearly every day.
• Recurrent thoughts of death or suicide, suicidal ideation, suicide planning, or a suicide attempt.

Simply counting symptoms is not sufficient. The presentation must represent a clinically significant change from previous functioning and must cause significant distress or impairment in social, occupational, or other important areas. In addition, the syndrome must not be better attributable to the physiological effects of a substance or another medical condition.

It is important to distinguish these requirements for the episode from the criteria used to diagnose major depressive disorder. The latter requires that the presentation not be better explained by specified schizophrenia spectrum or psychotic disorders and, above all, that there has never been a manic or hypomanic episode not attributable to substances or other physiological conditions. The presence of a manic episode identifies bipolar I disorder, whereas a history of hypomania associated with a major depressive episode points toward bipolar II disorder.

Assessment for mania and hypomania should not rely on the generic question of whether the patient has ever had periods when they “felt very well.” Distinct episodes of elevated, expansive, or persistently irritable mood associated with abnormally increased energy or activity, decreased need for sleep, increased talkativeness, accelerated thinking, grandiosity, increased goal-directed activities, or impulsive and risky behavior must be investigated.

Particular attention is required in the presence of very early depressive onset, high recurrence, family history of bipolar disorder, psychotic symptoms, mixed features, hypersomnia and hyperphagia, postpartum depression, or previous mood switching during antidepressant treatment. These features do not diagnose bipolar disorder, but they increase the need for a thorough longitudinal history.

Screening questionnaires for bipolarity can help identify patients who warrant further assessment, but they cannot independently confirm a diagnosis. CANMAT emphasizes that tools such as the Mood Disorder Questionnaire have limitations in sensitivity and specificity and must be interpreted in the context of the clinical interview.

ICD-11 has some differences from DSM-5-TR that should be understood to avoid inappropriate overlap. In the ICD-11 definition of a depressive episode, ten domains are considered because hopelessness is treated as a specific symptom in addition to the other affective, cognitive, psychomotor, and neurovegetative domains. ICD-11 also requires at least five symptoms and at least one of depressed mood or diminished interest or pleasure, present for most of the day, nearly every day, for at least two weeks.

ICD-11 also uses the depressive episode to characterize single episode depressive disorder, recurrent depressive disorder, and depressive phases of bipolar disorders. ICD-11 categories and qualifiers should not be automatically translated into DSM-5-TR specifiers because, although the two systems have been harmonized in many respects, they are not identical.

Once the syndrome has been recognized, the second diagnostic level is to define severity, safety, and associated features. Psychotic symptoms, mixed features, catatonia, impaired food and fluid intake, inability to care for oneself, and major cognitive changes must be directly assessed.

Assessment of suicide risk is mandatory. The interview must explore passive and active ideation, intent, planning, access to means, preparatory behaviors, previous attempts, recent escalation of symptoms, alcohol or other substance use, agitation, impulsivity, psychosis, hopelessness, and protective factors. Information from family members or other people may be particularly important when the patient is severely impaired, psychotic, catatonic, or poorly cooperative.

Risk scales should not be used to predict with certainty who will die by suicide, nor as the sole criterion for discharge, hospitalization, or intensity of care. The decision must derive from an individualized clinical formulation that considers the context, the possibility of reducing modifiable factors, and the ability to ensure safety and follow-up.

Scales such as the PHQ-9, Hamilton Depression Rating Scale, and Montgomery-Åsberg Depression Rating Scale can be useful for screening, quantifying severity, or monitoring response, but they are not pathognomonic tests. A high score increases the probability of a depressive syndrome and requires clinical assessment, whereas an isolated score establishes neither the diagnosis nor the unipolar or bipolar nature of the episode.

The third level consists of assessing possible secondary causes and comorbidities. The medical history should investigate endocrine, neurological, oncological, inflammatory, and systemic diseases, chronic pain, sleep disorders, and recent changes in general health. All prescription medications, over-the-counter products, psychoactive substances, and alcohol use should be documented.

The general and neurological physical examination should be guided by the clinical history. CANMAT recommends a targeted medical work-up and notes that a complete blood count and TSH are low-cost tests useful, respectively, for identifying anemia and thyroid dysfunction that may contribute to symptoms such as fatigue and reduced energy. Additional tests should be selected according to clinical suspicion rather than applied indiscriminately to all patients.

Depending on the context, electrolytes, renal and liver function, glucose, vitamin B12, folate, pregnancy testing, toxicology, or other investigations may be indicated, but no universal panel is required to diagnose a major depressive episode. Selection should be based on the history, age, comorbidities, physical examination, medications used, and realistically plausible differential diagnoses.

Electroencephalography, brain neuroimaging, and electrocardiography are not part of the routine diagnosis of a depressive episode. Magnetic resonance imaging or other neurological investigations may become appropriate in the presence of focal neurological signs, new persistent cognitive decline, sudden changes in personality or behavior, atypical onset, or other features suggesting brain disease.

Differential diagnosis with bereavement requires caution. Bereavement does not automatically exclude a major depressive episode, and the DSM no longer contains a time rule preventing diagnosis in the weeks after a loss. In uncomplicated grief, emotional states often tend to occur in waves related to memories of the deceased person, self-esteem is generally preserved, and thoughts are centered on the loss; however, there is substantial overlap and judgment must be based on the entire clinical picture.

Adjustment disorder may cause depressed mood in relation to an identifiable stressor, but if the full criteria for another disorder are met, classification must be reconsidered. The presence of a stressor alone does not make depression simply an adjustment disorder.

Anxiety disorders, post-traumatic stress disorder, obsessive-compulsive disorder, and other conditions can cause insomnia, fatigue, cognitive difficulties, and social withdrawal. Diagnosis depends on identifying the predominant syndrome and any concurrent presence of multiple disorders, because comorbidity is common.

Psychotic disorders require reconstruction of the temporal relationship between affective symptoms and psychosis. If delusions or hallucinations occur exclusively during the depressive episode, they may be compatible with depression with psychotic features; the presence of significant periods of psychosis independent of mood disturbance instead points toward other diagnoses, including schizoaffective disorder.

In older patients or those with cognitive deficits, neurodegenerative diseases, delirium, and other neurological disorders must be considered. Depression and neurocognitive disorder can coexist, and improvement in affective symptoms does not necessarily guarantee complete cognitive normalization.

The final diagnosis is therefore the result of a sequence: identification of the depressive syndrome, assessment of severity and risk, reconstruction of the longitudinal history, investigation of mania or hypomania, reasoned exclusion of substances and medical conditions, and distinction from other psychiatric disorders. No single pathognomonic test can replace this process.

Clinical specifiers

Once the depressive episode has been identified, the diagnostic label alone does not adequately describe the clinical presentation. DSM-5-TR uses several specifiers to characterize symptoms, severity, and course. These features may modify prognosis, risk, and treatment choice, but they should not be confused with independent diseases.

Severity is defined by integrating the number of symptoms, their intensity, and functional impairment. A mild episode has relatively few symptoms beyond the diagnostic threshold, manageable intensity, and limited impairment; a moderate episode occupies an intermediate position; a severe episode is characterized by numerous intense symptoms and marked distress or disability. The presence of psychosis is specified separately and is not simply synonymous with the quantitative level of severity.

During follow-up, partial remission may be indicated when all criteria for the episode are no longer met but clinically relevant symptoms persist, or when an insufficient period has elapsed without significant symptoms. Full remission instead indicates the absence of significant signs or symptoms of the episode for the period specified by the diagnostic system. Remission does not necessarily mean definitive recovery from the underlying disorder.

The with anxious distress specifier describes the presence during the episode of at least two manifestations including tension, unusual restlessness, difficulty concentrating because of worry, fear that something terrible may happen, or a feeling of losing control. The number and intensity of symptoms allow the anxious component to be graded further.

This component is clinically important because marked anxiety may be associated with greater distress, poorer functioning, and greater therapeutic complexity. It does not, however, replace the diagnosis of a possible comorbid anxiety disorder, which should be made separately when its criteria are met.

The with mixed features specifier is used when, during most days of the depressive episode, at least three manic or hypomanic symptoms that do not completely overlap with depressive symptoms are present. These include elevated or expansive mood, grandiose self-esteem, increased talkativeness, accelerated thinking, increased energy or goal-directed activity, greater involvement in potentially harmful activities, and decreased need for sleep.

The presence of mixed features deserves particular attention because it may signal greater phenotypic proximity to the bipolar spectrum and has prognostic and therapeutic implications. If the full criteria for a manic or hypomanic episode are met, the presentation should not be artificially maintained as simple unipolar depression with mixed features.

Melancholic features require an almost complete loss of pleasure in activities or lack of reactivity to usually pleasurable stimuli, accompanied by at least three additional features among a distinct quality of depressed mood, morning worsening, early awakening, marked psychomotor disturbance, anorexia or weight loss, and intense or inappropriate guilt.

Melancholia is frequently associated with greater expression of neurovegetative and psychomotor disturbances, but it should not be turned into a certain biological category. No endocrine, polysomnographic, or neuroimaging test can confirm the melancholic specifier in an individual patient.

Atypical features are defined first by mood reactivity, meaning the ability of mood to improve in response to actual or potential positive events. This must be accompanied by at least two of significant increase in appetite or weight, hypersomnia, a sensation of heaviness in the limbs, and a persistent pattern of marked interpersonal rejection sensitivity with functional consequences.

The term atypical does not mean that the presentation is rare or that all patients must simultaneously have hypersomnia and hyperphagia. Recognizing the phenotype may also be useful because some features, especially when associated with early onset and recurrence, should increase attention to possible bipolarity.

Psychotic features include delusions or hallucinations during the depressive episode. Their content may be mood-congruent, such as guilt, ruin, nihilism, death, or deserved punishment, or mood-incongruent. Psychotic depression is a clinically severe condition that requires specialist assessment and substantially changes treatment.

Psychosis should not be classified as a “complication” that necessarily develops after the episode: it may be an integral component of the phenotype of the episode itself. Likewise, the presence of psychosis must be distinguished from an independent psychotic disorder through the temporal relationship between psychotic symptoms and mood disturbance.

The with catatonia specifier requires the presence of at least three signs belonging to the catatonic syndrome. DSM-5-TR considers stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerisms, stereotypy, agitation not influenced by external stimuli, grimacing, echolalia, and echopraxia.

Catatonia must be recognized promptly because it can lead to prolonged immobility, dehydration, malnutrition, thromboembolism, pressure ulcers, infections, and autonomic instability. Diagnosis also requires exclusion of medical and neurological causes and related syndromes.

The DSM-5-TR with peripartum onset specifier applies when the episode begins during pregnancy or within the first four weeks after delivery. This window is narrower than the clinical and care concept of perinatal depression used by many guidelines, which includes a broader postpartum interval, often up to twelve months.

The terminological difference is important. An episode beginning several months after delivery may be clinically considered postpartum or perinatal depression according to guidelines and studies while not meeting the DSM specifier for peripartum onset. The two definitions should therefore not be considered equivalent.

During the perinatal period, it is particularly important to investigate manic, hypomanic, or psychotic symptoms because some presentations initially interpreted as unipolar depression belong to the bipolar spectrum. Postpartum psychosis, marked agitation, confusion, or rapid mood changes require urgent assessment.

Seasonal pattern does not simply describe the occurrence of a single episode in winter. In the DSM it is applied to the course of recurrent major depressive disorder or bipolar disorders when there is a regular temporal relationship between episodes and specific seasons, with remissions or changes in polarity also linked to the time of year.

To identify a seasonal pattern, the temporal relationship must have occurred during the previous two years without nonseasonal episodes in the same interval and, considering the entire course, seasonal episodes must substantially outnumber nonseasonal episodes. Psychosocial events that regularly recur in the same season may provide an alternative explanation and should be considered.

Characterization with a specifier must always follow definition of the underlying disorder. Saying that an episode has melancholic, psychotic, or mixed features describes its phenotype, whereas defining a disorder as major depressive, bipolar I, or bipolar II requires longitudinal information extending beyond the current episode.

Different specifiers may also coexist when their respective requirements are met. An episode may, for example, be severe and present with anxiety and psychotic features. A complete description allows the clinical presentation to be communicated more precisely and helps identify features requiring specific interventions.

Their usefulness nevertheless remains primarily clinical and descriptive. Specifiers do not necessarily correspond to independent etiological entities and do not have sufficiently validated individual biomarkers. Assessment should therefore remain anchored in phenomenology, course, and treatment response.

Treatment and prognosis

There is no single treatment for a major depressive episode independent of the diagnostic context. The first therapeutic decision is to determine whether the episode belongs to major depressive disorder, a bipolar disorder, or another condition, because strategies appropriate for unipolar depression may be inadequate in bipolar depression. Severity, suicide risk, psychosis, catatonia, comorbidities, previous responses, patient preferences, and treatment availability must all be integrated into the choice.

Before any pharmacological algorithm is applied, safety must be ensured. Suicidal ideation with significant intent, inability to ensure one’s own safety, severe self-neglect, refusal of food or fluids, catatonia, severe psychosis, or rapid deterioration may require urgent assessment, intensification of care, or hospitalization. The decision must be individualized and should not derive solely from a risk score.

A safety plan may include identification of warning signs, coping strategies, people and services to contact, reduction of access to lethal means, and arrangement of close follow-up. Continuity of care is particularly important during transitions between services and after hospital discharge.

In major depressive disorder, contemporary guidelines recommend shared decision-making between psychological and pharmacological interventions based on severity and individual characteristics. NICE pragmatically distinguishes less severe from more severe forms and recommends not routinely offering an antidepressant as initial treatment for less severe depression unless the patient specifically prefers it.

For less severe episodes, structured psychological interventions may be appropriate, including guided self-help programs based on evidence-based principles, behavioral activation, cognitive behavioral therapy, and other validated psychotherapies. Choice, availability, preferences, previous treatments, and clinical characteristics should guide selection.

Cognitive behavioral therapy is among the most extensively studied interventions. It addresses dysfunctional cognitive patterns, rumination, avoidance, and behaviors that contribute to maintaining depression. Large meta-analyses of randomized studies confirm its efficacy in adult depression, while also showing considerable heterogeneity of effects and the importance of methodological study quality.

Behavioral activation aims progressively to restore meaningful activities and sources of positive reinforcement, counteracting avoidance and inactivity. Interpersonal therapy instead addresses relational problems and role changes associated with the episode. Both have clinical evidence and appear among the psychotherapies recommended by major guidelines.

In moderate or severe episodes, and more generally when impairment is substantial, antidepressant pharmacotherapy may be indicated, alone or combined with psychotherapy. Combining an antidepressant with psychotherapy is one of the initial strategies considered for more severe depression and may offer advantages particularly when symptoms are numerous, impairment is substantial, or response to a single treatment modality is incomplete.

Drugs commonly used as first-line treatment in major depressive disorder include SSRIs, SNRIs, and several second-generation antidepressants, including bupropion, mirtazapine, and vortioxetine according to CANMAT. Selection of the individual agent should consider previous responses, adverse-effect profile, comorbidities, interactions, predominant symptoms, preferences, and risk in overdose.

Response to antidepressants is not immediate and should be assessed longitudinally, verifying adherence, tolerability, dose, and adequate treatment duration. Initial monitoring should include any worsening of agitation, changes in suicidal ideation, adverse effects, and emergence of manic or hypomanic symptoms.

When response is insufficient, diagnostic accuracy, adherence, dose, duration, substance use, comorbidities, and psychosocial factors should be reviewed before declaring treatment ineffective. Apparently resistant depression may reflect unrecognized bipolarity, a concomitant disorder, inadequate medication exposure, or other modifiable factors.

In the event of nonresponse or partial response, optimization of the current therapy, switching to another antidepressant, combination with psychotherapy, or augmentation strategies may be considered. CANMAT includes aripiprazole and brexpiprazole among the main evidence-supported adjunctive pharmacological options for major depression that does not respond adequately to an antidepressant, while other strategies have differing levels of evidence and tolerability.

Lithium, certain second-generation antipsychotics, thyroid hormone in selected settings, and other strategies may be used in difficult-to-treat depression, but they require specific assessment of efficacy, safety, and monitoring. Polypharmacy should not be accumulated automatically: every medication should retain a verifiable clinical rationale.

Repetitive transcranial magnetic stimulation is a noninvasive neuromodulation therapy with documented efficacy, particularly used when one or more pharmacological treatments have not produced an adequate response. The technique, cortical target, and stimulation protocol should be selected in a specialist setting.

Electroconvulsive therapy remains one of the most effective treatments for some severe forms of depression. NICE recommends considering it when a rapid response is needed, when other treatments have failed, or when the adequately informed patient prefers it in the context of severe depression. It is particularly relevant in psychotic or catatonic presentations, severe nutritional impairment, or high clinical risk.

The decision to use ECT should include anesthetic and medical assessment, discussion of benefits and risks, consent according to the clinical and regulatory framework, and monitoring of cognitive effects. After an acute response, a continuation strategy should be planned because the risk of relapse may be high in the absence of subsequent treatment.

Intranasal esketamine is a specialist therapeutic option for adults with treatment-resistant major depressive disorder according to applicable regulatory indications. In the European Union, the drug is used in combination with oral antidepressant therapy and requires administration and monitoring in a healthcare setting because of effects such as sedation, dissociation, and blood-pressure changes.

Intravenous racemic ketamine has evidence of rapid antidepressant efficacy in specialist settings, but availability, regulatory indications, and protocols differ from those of approved esketamine. The two strategies should not be regarded as pharmacologically or regulatorily interchangeable.

In psychotic depression, guidelines support the combination of an antidepressant and an antipsychotic or, when clinically indicated, ECT. An antidepressant alone may be insufficient to treat the psychotic component. Choice should take into account severity, risk, tolerability, and the need for a rapid response.

When catatonia is present, treating depression alone is not sufficient. British Association for Psychopharmacology guidelines identify benzodiazepines, particularly lorazepam, and ECT as key treatments for the catatonic syndrome. Dehydration, malnutrition, prolonged immobility, autonomic instability, or malignant catatonia increase the urgency of intervention.

If the depressive episode belongs to a bipolar disorder, the treatment algorithm changes substantially. CANMAT/ISBD guidelines include drugs such as quetiapine, lithium, lamotrigine, and lurasidone in specific modes of use among first-line options for bipolar I depression. Antidepressants should not automatically be prescribed as monotherapy as if the patient had unipolar depression, particularly in the presence of mixed features or a risk of mood switching.

Recognizing bipolarity is therefore one of the most important therapeutic steps. An unusually activating response to antidepressants, a history of hypomania, bipolar family history, or mixed features should prompt diagnostic reassessment before simply intensifying antidepressant pharmacotherapy.

During pregnancy and the postpartum period, assessment must balance the risks of untreated illness against the specific risks of available interventions. ACOG guidelines emphasize that effective treatments should not be stopped automatically solely because of pregnancy or breastfeeding; the choice should consider clinical history, severity, previous response, pharmacological profile, and patient preferences.

Lifestyle interventions, regular physical activity, sleep regularization, reduction of alcohol and substance use, and treatment of comorbidities may contribute to overall management, but in moderate or severe presentations they should not be presented as automatic substitutes for psychological or pharmacological treatments of proven efficacy.

Once remission has been achieved, treatment should not be stopped immediately. The continuation phase aims to consolidate the response and prevent relapse of the same episode. Duration should be individualized according to the number of previous episodes, severity, residual symptoms, suicide risk, comorbidities, and likelihood of recurrence.

In patients with recurrent episodes, high severity, or persistent risk factors, prolonged maintenance treatment may be indicated. The decision should be reassessed periodically and accompanied by monitoring of adverse effects and patient preferences.

The prognosis of a major depressive episode is highly variable. Some patients achieve full remission after a single treatment, others require several sequential strategies, while a proportion develop persistent residual symptoms or a recurrent course. The STAR*D study showed in a large pragmatic sample that the probability of remission progressively decreases when several successive treatment steps are required.

Residual symptoms are particularly important prognostically because they are associated with persistent impairment and a greater risk of relapse. Assessment of response should therefore not be limited to the percentage reduction on a scale but, whenever possible, should aim for clinical remission and functional recovery.

Previous episodes, early onset, high severity, psychosis, psychiatric or medical comorbidity, persistent psychosocial stress, residual symptoms, and incomplete treatment response are associated with a less favorable course. None of these factors, however, allows a certain prediction for an individual patient.

A favorable prognosis depends on diagnostic accuracy, identification of bipolarity when present, prompt treatment of severe forms, adherence, continuity of care, and availability of subsequent strategies when the first intervention does not produce remission. Monitoring should continue even after improvement of the acute episode.

Complications

The most serious clinical consequence associated with a major depressive episode is suicidal behavior. Major depression is one of the main psychiatric disorders associated with suicidal ideation, attempts, and death by suicide, but risk is highly heterogeneous. Previous attempts, current ideation with intent, hopelessness, substance use, agitation, impulsivity, psychosis, and comorbidities may contribute to risk formulation.

Suicide should not be regarded as the inevitable outcome of a severe episode, nor can it be predicted with certainty using a scale. Prevention requires repeated assessments, intervention on modifiable factors, effective treatment of the underlying disorder, restriction of access to lethal means when possible, and a care network capable of responding to clinical changes.

In the most severe presentations, profound self-neglect may occur. Loss of energy, apathy, psychomotor retardation, hopelessness, and impaired decision-making can prevent the patient from eating, drinking, correctly taking necessary medications, or maintaining normal personal hygiene.

Marked reduction in food intake may cause weight loss, malnutrition, electrolyte disturbances, and dehydration. These risks are particularly relevant in older, frail, psychotic, or catatonic patients and may necessitate inpatient management independently of the subjective intensity of sadness.

Catatonia, when present as a syndrome associated with the episode, may cause complications secondary to immobility and reduced food intake, including venous thromboembolism, infections, pressure injuries, contractures, dehydration, and metabolic disturbances. Forms with autonomic instability can become medical emergencies.

Functional impairment may affect every area of life. Absenteeism, reduced productivity, academic difficulties, job loss, inability to manage financial resources properly, and reduced social participation may result from the combination of anhedonia, fatigue, indecisiveness, and attentional deficits.

Family and intimate relationships may deteriorate because of withdrawal, irritability, reduced libido, loss of initiative, and negative beliefs about oneself and others. Interpersonal impairment may in turn reduce social support and contribute to persistence of symptoms, creating a mutually reinforcing cycle.

Problematic use of alcohol or other substances may occur as a comorbidity or be used by the patient in an attempt to modulate insomnia, anxiety, or emotional distress. This behavior can worsen mood, disrupt sleep, reduce treatment adherence, increase impulsivity and suicide risk, and complicate diagnosis.

Depression and medical illnesses have bidirectional relationships. Depressive symptoms can reduce physical activity, treatment adherence, and self-care, while chronic illnesses, pain, and disability can worsen depression. At the population level, major depressive disorder is associated with increased morbidity and mortality, but these associations arise from multiple biological, behavioral, and social mechanisms and cannot be attributed to a single cause.

Residual cognitive symptoms may persist even after mood improves and interfere with return to work or study. In older patients, persistent cognitive deficits also require reconsideration of the possibility of a concomitant neurocognitive disorder.

Another possible outcome is failure to achieve full remission. Persistent subthreshold symptoms can maintain significant disability and increase vulnerability to a subsequent exacerbation. For this reason, the therapeutic goal should not merely be to reduce episode severity but to achieve the most complete symptomatic and functional recovery possible.

Recurrence is one of the main long-term problems. An individual who has experienced a major depressive episode may develop others, particularly when there have been multiple previous episodes, residual symptoms, or persistent vulnerability factors. Probability varies widely among patients and should not be expressed as a universal percentage applied indiscriminately to an individual case.

The recurrence of apparently depressive episodes also makes it essential to review the history periodically for hypomania or mania. Some patients initially classified as having unipolar depression may later manifest sufficient features for a bipolar diagnosis.

In presentations with psychotic features, impairment may be particularly profound. Delusions of guilt, ruin, or nihilism may increase refusal of treatment, food, or fluids and contribute to suicide risk. Treating the psychotic component is therefore an integral part of preventing medical and behavioral consequences.

During the postpartum period, a severe episode may impair the mother’s ability to care for herself and the newborn. When psychosis, confusion, mania, marked agitation, or thoughts of harming herself or the infant occur, urgent assessment is necessary because the presentation may belong to a high-risk condition requiring immediate specialist management.

A prolonged episode may lead to progressive loss of daily routines, reduced relationships, and difficulty with social reintegration even after the most evident symptoms improve. Functional rehabilitation and recovery of meaningful activities should therefore accompany purely symptomatic assessment.

Iatrogenic complications should be prevented through appropriate treatment selection. Metabolic, sexual, gastrointestinal, cardiovascular, neurological, or cognitive effects depend on the treatment used and patient characteristics. Adequate monitoring reduces the risk that adverse effects will lead to discontinuation, poor adherence, or worsening quality of life.

Particular attention is required when discontinuing antidepressants, which in some patients can produce a discontinuation syndrome. The onset of symptoms after dose reduction or cessation should not automatically be interpreted as depressive recurrence; timing, type of symptoms, and their course in relation to dosage changes help distinguish the two.

Similarly, the emergence of mania or hypomania during treatment requires diagnostic reassessment. The phenomenon may represent expression of bipolar vulnerability and changes the subsequent treatment strategy. Automatically continuing antidepressant escalation without reassessing the clinical picture may be inappropriate.

Prevention of complications therefore depends on early identification of the episode, correct diagnosis of the underlying disorder, systematic risk assessment, treatment proportionate to severity, and follow-up even after remission. A major depressive episode should be regarded as a potentially serious but treatable syndrome whose evolution cannot be understood without integrating current phenomenology and longitudinal course.

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