Major Depressive Episode

In medicine, the term depression refers to an actual psychiatric illness, often severely disabling, whose central clinical form is represented by the major depressive episode.

A major depressive episode is diagnosed when, for at least two consecutive weeks, the clinical picture is dominated by a depressed mood (or irritability in children and adolescents) and/or a marked loss of interest or pleasure in almost all activities, accompanied by at least four of the following symptoms:

1. Significant changes in appetite, resulting in weight fluctuations;
2. Sleep disturbances (insomnia or hypersomnia);
3. Psychomotor agitation or retardation, observable by others;
4. Fatigue or loss of energy (anergia);
5. Feelings of worthlessness or excessive/inappropriate guilt, sometimes delusional;
6. Difficulty concentrating, slowed thinking, or indecisiveness;
7. Suicidal ideation, with or without a specific plan, or suicide attempts.

For a valid diagnosis, these symptoms must represent a clear change from premorbid functioning, with significant impairment in social, occupational, or personal functioning. In some cases, although the individual may appear functionally intact, this condition is maintained only through tremendous internal effort. In severe cases, there may be complete neglect of self-care (nutrition, hygiene, clothing).

It is essential to exclude the possibility that the symptoms meet criteria for a mixed episode, are due to substance use (medications, drugs), underlying medical conditions (e.g., hypothyroidism), or are better explained by bereavement or transient life events.

In some individuals, depressive symptoms present predominantly as somatic complaints; in children and adolescents, marked irritability is common. Loss of interest or pleasure is almost always present, often noticed by family members before the patient themselves, with behaviors such as social withdrawal and abandonment of usual activities. Reduced sexual desire may also occur.

Appetite changes usually present as decreased appetite, but may also involve increased intake or cravings for specific foods. In children, severe appetite disturbance can interfere with achieving normal weight milestones.

Insomnia is the most common sleep disturbance and may present as:

• Initial insomnia: difficulty falling asleep;
• Middle insomnia: frequent awakenings with difficulty returning to sleep;
• Terminal insomnia: early morning awakening with inability to resume sleep.

Hypersomnia is less common but may involve prolonged nighttime sleep or excessive daytime sleeping. In many cases, sleep disturbance is the main reason for seeking medical help.
Polysomnographic studies reveal sleep abnormalities in 40–60% of outpatients and in up to 90% of hospitalized patients, with the following common findings:

1. Impaired sleep continuity: prolonged latency, frequent awakenings, early morning arousal;
2. Reduced slow-wave sleep (NREM stages 3 and 4);
3. Shortened REM latency and increased phasic REM activity (more rapid eye movements);
4. Prolonged duration of REM sleep during the first half of the night.

Psychomotor changes may manifest as either agitation or retardation. To be clinically relevant, they must be observable by others and not just subjectively reported. Common symptoms include reduced vitality, fatigue, and tiredness even without physical exertion.

Feelings of worthlessness and guilt often appear exaggerated or inappropriate and may even become delusional. The individual may interpret neutral events as evidence of their unworthiness or feel disproportionately guilty about past mistakes, taking on excessive responsibility for negative outcomes.

Concentration is often impaired. Patients report difficulty thinking, making decisions, and remembering. In elderly individuals, these symptoms may mimic early dementia, complicating differential diagnosis.

Thoughts of death are common and range in severity. They may involve beliefs that others would be better off without the person, recurrent suicidal ideation without a specific plan, or the presence of a detailed and concrete plan, sometimes including the acquisition of suicide means (e.g., rope, firearm). The risk increases with the specificity of the plan and availability of means, but it is impossible to predict with certainty whether or when the act will be carried out.

Suicidal ideation may stem from feelings of helplessness in the face of seemingly insurmountable difficulties or from the desire to end an intolerable emotional state. In such cases, prompt clinical intervention is critical.

Individuals with a major depressive episode often experience tearfulness, irritability, rumination, anxiety, obsessive health concerns, and difficulties in interpersonal and social relationships. Academic or occupational issues are common, as well as substance abuse and increased healthcare utilization.

Depressive symptoms typically develop over a few days or weeks, often preceded by a prodromal phase with mild anxiety and low mood, which can last for weeks or months. If untreated, a major depressive episode generally lasts over 4 months. Approximately 70–80% of patients achieve full remission, while 20–30% may have persistent subclinical symptoms lasting months or years without meeting full diagnostic criteria.

The pathophysiology of major depressive episodes involves dysregulation of neurotransmitter systems, particularly serotonin, norepinephrine, dopamine, acetylcholine, and GABA. Neuropeptides (e.g., CRH), HPA axis dysregulation, glucocorticoid hypersecretion, and attenuated responses to GH, TSH, and prolactin stimulation tests have also been implicated.

Some patients exhibit altered brain metabolism and blood flow, with increased activity in limbic and paralimbic regions and reduced activity in lateral prefrontal areas. In elderly individuals, depression may be associated with periventricular vascular lesions and other brain structural changes, suggesting overlap with cerebrovascular disease.

Clinical Specifiers

The major depressive episode can present in a variety of clinical forms that influence severity, duration, and therapeutic approach. When the episode represents the most recent manifestation within a mood disorder, it can be further characterized by clinical specifiers.

Based on symptom presence, three levels of severity are defined:

• Mild: when only 5 or 6 symptoms are present and functional impairment is minimal or absent, even if maintained through great effort.
• Moderate: intermediate severity between mild and severe forms, with more pronounced symptoms and initial functional impairment.
• Severe: meets most diagnostic criteria with evident impairment in daily life. It may occur:
  • with psychotic features: presence of delusions or hallucinations, typically consistent with depressive themes (guilt, ruin, nihilism), though sometimes inconsistent (persecution, thought insertion).
  • without psychotic features: absence of psychotic symptoms despite severe depressive presentation.

Based on course, the episode may also be specified as:

• In full remission: no significant depressive symptoms for at least two months.
• In partial remission: presence of residual symptoms not meeting full diagnostic criteria or remission lasting less than two months.
• Chronic: persistence of full criteria for major depressive episode for at least two years without remission periods.

Phenotypic Specifiers

Beyond severity and course, the episode may also be classified according to additional clinical features:

1. With catatonic features: includes marked psychomotor abnormalities such as immobility (catalepsy), purposeless motor activity, mutism, mannerisms, echolalia, or echopraxia.
2. With melancholic features: loss of pleasure and emotional reactivity, worse symptoms in the morning, early morning awakening, anorexia, marked psychomotor slowing, and excessive guilt. One of the most severe forms, with high suicide risk.
3. With atypical features: mood reactivity to positive events, hypersomnia, hyperphagia, heaviness in limbs (“leaden paralysis”), and hypersensitivity to rejection. More frequent in younger patients and may coexist with anxiety disorders.
4. With postpartum onset: begins within the first 4 weeks after delivery, marked by mood instability, anxiety, emotional lability, concern for the infant, up to delusions. Distinguished from the more common and benign “baby blues,” which affects up to 70% of women within the first 10 days post-delivery and does not impair global functioning.

Accurate specification is essential for proper treatment planning and prognosis. Episodes with melancholic or catatonic features, psychotic symptoms, or postpartum onset require thorough specialist evaluation and often more intensive, multimodal treatment approaches.

Pathophysiology and Neurobiological Aspects

Major depressive episodes are not merely subjective psychological states but reflect complex neurobiological alterations affecting mood, motivation, and stress response systems.

Pathophysiologically, there is dysregulation of key neurotransmitters involved in mood modulation:

• Serotonin (5-HT): reduced synaptic availability, especially in the raphe nuclei and limbic areas; associated with anhedonia, impulsivity, and obsessive symptoms.
• Norepinephrine (NA): decreased activity in the locus coeruleus and cortical projections, linked to energy loss, cognitive deficits, and attention impairment.
• Dopamine (DA): mesocorticolimbic hypofunction, implicated in anhedonia, psychomotor slowing, and motivational deficits.

Also implicated are:

• GABA (gamma-aminobutyric acid): decreased cortical inhibitory activity, leading to increased excitability and associated anxiety.
• Acetylcholine: relative hyperactivity, particularly in psychotic or melancholic depression.
• Neuropeptides: such as CRH (corticotropin-releasing hormone), which contributes to chronic HPA axis activation.

HPA axis hyperactivity is commonly observed, with:

• Elevated plasma and urinary cortisol levels.
• Reduced suppression in the dexamethasone suppression test.
• Altered endocrine responses (GH, TSH, prolactin).

Functional neuroimaging has shown abnormalities in brain metabolism and blood flow:

• Increased activity in limbic and paralimbic areas (amygdala, hippocampus, anterior cingulate cortex), involved in emotional processing.
• Decreased activity in the dorsolateral prefrontal cortex, linked to cognitive deficits, slowing, and indecision.

In elderly patients, late-onset depression may be associated with structural brain changes, particularly periventricular white matter lesions, suggesting a possible “vascular” component in the pathophysiology of some depressive forms.

Clinical Course and Prognosis

The clinical course of a major depressive episode is highly variable among individuals. In most cases, symptoms develop over the course of days or weeks, often preceded by a prodromal phase with sleep disturbances, anxiety, irritability, or reduced energy.

Without treatment, the average episode lasts about 4–9 months, but in some cases may persist for years. Most patients achieve complete remission, but about 20–30% have persistent residual symptoms (such as anergia, sleep disturbances, or cognitive deficits) even after acute resolution.

Recurrence is common: about 50% of individuals who experience a major depressive episode will have another in their lifetime, and the risk increases after two or more episodes. Risk factors for recurrence include:

• Early onset.
• Severity of the initial episode.
• Psychiatric or medical comorbidities (e.g., anxiety disorders, chronic somatic illnesses).
• Lack of social support.

Prognosis improves with early diagnosis and appropriate treatment, which includes pharmacotherapy, psychotherapy, and, in selected cases, integrated strategies or physical therapies (vagal nerve stimulation, TMS, ECT).

Suicide risk, although not easily predictable, is significantly increased in depressed individuals, particularly in those with marked anhedonia, social isolation, psychotic symptoms, or multiple treatment failures.

Timely care, continuity of follow-up, and personalized treatment plans are key for effective management and favorable outcomes.

Differential Diagnosis

Diagnosing a major depressive episode requires thorough evaluation, as depressive symptoms may occur in many other pathological contexts. Therefore, accurate clinical differentiation is essential to exclude conditions that mimic a major depressive episode but require different therapeutic approaches.

1. Normal Grief: mourning the loss of a loved one may cause deep sadness, insomnia, and loss of appetite. However, in normal grief:

• Depressed mood is variable and tends to improve over time.
• Self-esteem is generally preserved.
• Pathological guilt or worthlessness is absent.
• Thoughts of death are centered on “reunion” with the deceased, not on active suicidal intent.

2. Depressive Episode in Bipolar Disorder: the clinical picture may be indistinguishable from unipolar depression. However, a history of manic, hypomanic, or mixed episodes confirms a diagnosis of bipolar disorder (type I or II depending on severity and type of manic episodes).

3. Anxiety and Somatic Symptom Disorders: chronic anxiety can cause fatigue, insomnia, cognitive difficulties, and social withdrawal. Somatic symptom disorders (especially somatization) can resemble depression, but focus is on physical symptoms, often multiple and resistant to medical investigation.

4. Dementias: in the elderly, especially early on, major depression may mimic a dementing syndrome (“depressive pseudodementia”). The key difference is that cognitive deficits in depression are often fluctuating, reversible, and accompanied by anhedonia, psychomotor slowing, and disengagement from performance.

5. General Medical Conditions: endocrine disorders (hypothyroidism, Cushing’s), neurologic diseases (stroke, multiple sclerosis, Parkinson’s), and cancers may present with depressive symptoms. These are typically accompanied by characteristic somatic signs and do not respond to standard antidepressant treatment. Thorough lab and imaging evaluation is critical.

6. Medications and Substances: many drugs (beta-blockers, corticosteroids, interferon, contraceptives, benzodiazepines) can induce depressive symptoms. Substance abuse or withdrawal (alcohol, cocaine, opioids) should always be investigated.

Conclusion

The major depressive episode is a complex disorder with multifaceted clinical manifestations and articulated neurobiological underpinnings. It requires accurate, multidimensional assessment, including clinical history, risk factors, exclusion of comorbid medical conditions, and careful differentiation from other psychopathological states.

Optimal management involves early diagnosis, structured and empathic care, and the use of integrated, personalized treatment strategies aimed at reducing chronicity, disability, and suicide risk.

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