Major Depressive Disorder

Overview

According to the National Institute for Health and Care Excellence (NICE, 2022), major depressive disorder is characterized by persistent low mood, loss of pleasure or interest in activities, and associated cognitive, behavioral, and physical symptoms that significantly impair functioning. Depression exists on a spectrum from mild to severe, with varying impacts on daily life (NICE, 2022). The condition affects individuals across all demographics and represents a leading cause of disability. MDD typically follows a recurrent course, with many individuals experiencing multiple episodes throughout their lifetime. Early recognition and appropriate intervention are essential for optimal outcomes and relapse prevention (NICE, 2022).

Diagnostic Criteria

The DSM-5 TR provides the following diagnostic criteria for the diagnosis of Major Depressive Disorder (MDD): i

Criteria A: Atleast five of the following symptoms during the same two-week period, and at least one of the symptoms must be either (1) depressed mood or (2) loss of interest or pleasure.

Core Clinical Features (Must have at least one)

1. Depressed Mood: Feeling sad, empty, hopeless, or appearing tearful most of the day, nearly every day. (In children and adolescents, this can manifest as an irritable mood).
2. Anhedonia: Significantly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day.

Physical and Cognitive Features

3. Weight or Appetite Changes: Significant weight loss when not dieting, weight gain, or a decrease/increase in appetite nearly every day.
4. Sleep Disturbance: Insomnia (difficulty sleeping) or hypersomnia (excessive sleeping) nearly every day.
5. Psychomotor Agitation or Retardation: Observable restlessness (e.g., pacing, inability to sit still) or being “slowed down” (e.g., slowed speech or movement), as noticed by others.
6. Fatigue: Loss of energy or daily fatigue, even without physical exertion.
7. Feelings of Worthlessness or Guilt: Excessive or inappropriate guilt (which may be delusional) or feeling worthless nearly every day.
8. Diminished Ability to Think: Diminished ability to concentrate, think clearly, or make decisions (often described as “brain fog”).
9. Suicidality: Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt/specific plan for committing suicide.

The APA guideline highlights several nuances regarding how these features present across different populations:

• Functional Impairment: The symptoms must cause “clinically significant distress or impairment” in social, occupational, or other important areas of functioning.
• The Three Age Cohorts: The guideline specifically analyzes these features across three groups—children/adolescents, adults, and older adults.
  • Children/Adolescents: Often present with irritability rather than sadness and may fail to make expected weight gains.
  • Older Adults: May present more frequently with somatic (physical) complaints and cognitive symptoms (pseudodementia) rather than overt sadness.
• Exclusion Criteria: The features must not be attributable to the physiological effects of a substance (e.g., drug abuse, medication) or another medical condition.

Epidemiology and Statistics

Major depressive disorder (MDD) presents a substantial and growing global public health challenge, with significant variations across regions and nations. According to Zhao et al. (2025), depressive disorders in adolescents and young adults have shown concerning trends from 1990 to 2021, reflecting an escalating burden worldwide.

Globally, MDD affects millions of individuals, with prevalence rates varying considerably by geographic region (Zhao et al., 2025). High-income regions typically report higher diagnosed prevalence, though this may partially reflect better detection and reporting systems rather than true epidemiological differences. The Global Burden of Disease Study 2021 data reveals that depressive disorders contribute substantially to years lived with disability (YLDs), particularly among younger populations (Zhao et al., 2025).

Regional analyses demonstrate heterogeneity in MDD burden, with certain areas experiencing disproportionately high rates. Nationally, prevalence estimates range significantly, influenced by socioeconomic factors, healthcare access, and cultural attitudes toward mental health (Zhao et al., 2025). The disability-adjusted life years (DALYs) attributable to depressive disorders have increased over the three-decade period, highlighting the expanding impact on population health. These epidemiological patterns underscore the urgent need for targeted, culturally appropriate interventions addressing the global MDD crisis.

Evaluation/Assessment Procedures

• Comprehensive psychiatric history: Including symptom onset, duration, severity, previous episodes, and family history of mental health disorders (NICE, 2022)
• Assessment of core depressive symptoms: Low mood, anhedonia, fatigue, sleep disturbance, appetite changes, concentration difficulties, guilt, and suicidal ideation
• Suicide risk assessment: Evaluate suicidal thoughts, plans, intent, previous attempts, and protective factors (NICE, 2022)
• Functional impairment evaluation: Impact on work, relationships, self-care, and social activities
• Screening for comorbid conditions: Anxiety disorders, substance use, personality disorders, and medical conditions (NICE, 2022)
• Physical examination and investigations: Rule out medical causes such as thyroid dysfunction, vitamin deficiencies, or other organic conditions
• Use of validated screening tools: Patient Health Questionnaire-9 (PHQ-9), Hospital Anxiety and Depression Scale (HADS), or Beck Depression Inventory (NICE, 2022)
• Assessment of psychosocial factors: Recent life events, stressors, social support, employment, housing, and financial circumstances
• Medication review: Current medications that may contribute to depressive symptoms
• Assessment of patient preferences: Treatment preferences, previous treatment experiences, and cultural considerations (NICE, 2022)
• Severity classification: Determine whether depression is mild, moderate, or severe to guide treatment selection

Etiology and Risk Factors

Major depressive disorder (MDD) arises from a complex interplay of biological, psychological, and environmental factors rather than a single causative agent. According to Mehra et al. (2025), genetic predisposition plays a significant role, with heritability estimates ranging from 37-40%, indicating substantial familial risk for developing the disorder.

Neurobiological factors contribute significantly to MDD’s etiology. Dysregulation of neurotransmitter systems, particularly serotonin, norepinephrine, and dopamine, forms a foundational component (Mehra et al., 2025). Additionally, structural and functional brain abnormalities in regions governing mood regulation, including the prefrontal cortex, hippocampus, and amygdala, have been implicated in the disorder’s development.

Environmental stressors serve as crucial triggers, with chronic stress, childhood trauma, and adverse life events significantly increasing MDD risk (Mehra et al., 2025). These experiences can induce lasting neurobiological changes through epigenetic modifications, altering gene expression without changing DNA sequences.

Psychosocial factors including social isolation, lack of support systems, and maladaptive cognitive patterns further contribute to vulnerability (Mehra et al., 2025). Medical comorbidities, particularly chronic illnesses and inflammatory conditions, also increase susceptibility to developing MDD. This multifactorial etiology underscores the need for comprehensive, individualized approaches to understanding and treating depression.

Pathophysiology

Major depressive disorder (MDD) involves complex pathophysiological mechanisms that evolve across clinical stages. The disorder’s progression reflects interconnected biological systems rather than a single causative pathway (De Menezes Galvão et al., 2021). The pathophysiology centers on monoaminergic dysfunction, particularly involving serotonin, norepinephrine, and dopamine neurotransmission (De Menezes Galvão et al., 2021). However, this represents only one component of a broader neurobiological cascade. The hypothalamic-pituitary-adrenal (HPA) axis dysregulation plays a crucial role, with chronic stress leading to sustained cortisol elevation that damages hippocampal neurons and impairs neuroplasticity (De Menezes Galvão et al., 2021).

Inflammatory processes significantly contribute to MDD’s pathophysiology. Elevated pro-inflammatory cytokines like IL-6 and TNF-α interact with neurotransmitter systems, creating a bidirectional relationship between immune activation and depressive symptoms (De Menezes Galvão et al., 2021). This inflammation affects tryptophan metabolism, reducing serotonin availability while increasing neurotoxic kynurenine pathway metabolites.

Neuroplasticity impairment, evidenced by reduced brain-derived neurotrophic factor (BDNF) levels, further compounds these mechanisms (De Menezes Galvão et al., 2021). This leads to decreased hippocampal volume and compromised synaptic plasticity, particularly in mood-regulating circuits.These pathophysiological features intensify across MDD’s clinical stages, from initial episodes through treatment-resistant forms, suggesting stage-specific interventions may optimize treatment outcomes (De Menezes Galvão et al., 2021).

Differential Diagnosis

According to Bains and Abdijadid (2020), establishing an accurate diagnosis of major depressive disorder requires careful differentiation from numerous conditions presenting with similar symptomatology. The key differential diagnoses include:

• Bipolar disorder: Depressive episodes in bipolar disorder are clinically indistinguishable from MDD; however, treatment approaches differ significantly. A thorough history exploring previous manic or hypomanic episodes is crucial .
• Persistent depressive disorder (dysthymia): Characterized by chronic depressive symptoms lasting at least two years but typically less severe than major depressive episodes.
• Adjustment disorder with depressed mood: Occurs in response to identifiable stressors and typically resolves within six months of stressor cessation.
• Medical conditions: Hypothyroidism, vitamin deficiencies (particularly B12 and folate), neurological disorders, and malignancies can mimic depressive symptoms.
• Substance-induced mood disorders: Depression secondary to alcohol, stimulants, or medications requires consideration.
• Anxiety disorders: Frequently coexist with MDD and may present with overlapping symptoms.
• Grief reactions: Normal bereavement versus pathological grief.
• Schizophrenia with depressive features
• Personality disorders: Particularly those presenting with mood dysregulation.

Psychotherapy

The National Institute for Health and Care Excellence (NICE, 2022) guidelines emphasize psychological interventions as first-line treatments for depression across severity levels. For mild to moderate depression, NICE recommends low-intensity psychosocial interventions, including individual guided self-help based on cognitive behavioral therapy (CBT) principles and group-based CBT programs (NICE, 2022). These approaches offer accessible, cost-effective options that empower patients with self-management skills.

For moderate to severe depression, high-intensity psychological interventions are recommended. CBT remains the most extensively evidenced therapy, targeting maladaptive thought patterns and behaviors that perpetuate depressive symptoms (NICE, 2022). Interpersonal therapy (IPT) addresses relationship difficulties and life transitions contributing to depression, while behavioral activation focuses on increasing engagement with rewarding activities to counter withdrawal and avoidance patterns.

NICE also recognizes alternative evidence-based approaches including behavioral couples therapy for individuals whose depression affects intimate relationships, and short-term psychodynamic psychotherapy for those preferring insight-oriented work (NICE, 2022). The guidelines stress matching therapy type to individual preferences, circumstances, and previous treatment responses. For chronic or recurrent depression, mindfulness-based cognitive therapy (MBCT) is recommended to prevent relapse, combining meditation practices with cognitive strategies to reduce vulnerability to future depressive episodes.

Psychopharmacology

The NICE (2022) guidelines provide comprehensive recommendations for antidepressant use in treating major depressive disorder. Pharmacological intervention is not routinely recommended for mild depression unless patients have a history of moderate to severe episodes or symptoms persist despite other interventions (NICE, 2022). For moderate to severe depression, antidepressants should be offered alongside high-intensity psychological interventions.

Selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line pharmacological treatment due to their favorable tolerability profile and safety in overdose (NICE, 2022). When prescribing antidepressants, clinicians should discuss potential benefits, risks, side effects, and the typical timeline for therapeutic response, which usually requires 2-4 weeks. Treatment should continue for at least six months after remission to prevent relapse.

If initial antidepressant therapy proves inadequate, NICE recommends several strategies including increasing the dose, switching to an alternative antidepressant (either within the same class or to a different class), or combining antidepressants (NICE, 2022). Augmentation strategies using medications like lithium, antipsychotics, or second antidepressants may be considered for treatment-resistant depression. The guidelines emphasize regular monitoring for efficacy, adverse effects, and suicide risk, particularly during treatment initiation and dose adjustments. Discontinuation should be gradual to minimize withdrawal symptoms.

Complementary Treatment

The NICE (2022) guidelines address complementary and alternative approaches to depression management with cautious, evidence-based recommendations. While acknowledging patient interest in such interventions, NICE emphasizes that complementary treatments should not replace evidence-based psychological or pharmacological therapies for moderate to severe depression.

Physical activity is strongly endorsed as a beneficial complementary intervention. NICE recommends structured group exercise programs for individuals with mild to moderate depression, as regular physical activity demonstrates significant antidepressant effects (NICE, 2022). Exercise interventions should be tailored to individual preferences and capabilities, promoting sustainable engagement.

Regarding herbal remedies, NICE advises against St. John’s Wort due to uncertainty about appropriate doses, significant drug interactions (particularly with antidepressants, oral contraceptives, and anticoagulants), and variable product quality (NICE, 2022). Healthcare professionals should actively inquire about patients’ use of herbal preparations to identify potential interactions.

Sleep hygiene interventions are recommended as supportive measures, given the bidirectional relationship between sleep disturbance and depression (NICE, 2022). Lifestyle modifications including balanced nutrition, stress management techniques, and social connection are recognized as valuable adjuncts to primary treatments. NICE emphasizes collaborative care approaches where complementary strategies support rather than substitute core evidence-based interventions, always considering individual patient preferences and circumstances when developing comprehensive treatment plans.

Prognosis 

The prognosis of major depressive disorder varies considerably based on multiple factors including treatment adherence, episode severity, and comorbid conditions. Bains and Abdijadid (2020) indicate that while many individuals experience significant improvement with appropriate treatment, MDD frequently follows a recurrent course. Approximately 50-85% of individuals who experience one major depressive episode will have at least one recurrence during their lifetime (Bains & Abdijadid, 2020).

With adequate treatment, most patients achieve symptom remission within several months. However, approximately one-third of individuals develop chronic or treatment-resistant depression requiring more intensive interventions (Bains & Abdijadid, 2020). Early age of onset, severe initial episodes, presence of psychotic features, and comorbid psychiatric or medical conditions generally predict poorer outcomes.

Several factors influence prognosis favorably, including strong social support systems, absence of comorbid substance use disorders, good treatment adherence, and access to quality mental healthcare (Bains & Abdijadid, 2020). Maintenance treatment following remission significantly reduces relapse risk. Unfortunately, MDD substantially increases suicide risk, with approximately 15% of individuals with severe depression dying by suicide. The disorder also contributes to increased mortality from cardiovascular disease and other medical conditions (Bains & Abdijadid, 2020). Early recognition, comprehensive treatment, and ongoing monitoring optimize long-term outcomes and quality of life for individuals living with MDD.

Red Flags/When to refer

According to the APA Clinical Practice Guideline for the Treatment of Depression, effective management requires a continuous “triage” mindset. Below, we break down the critical red flags and the specific clinical milestones that indicate a specialist referral is necessary.

1. The “Red Flags”: Immediate Risks

“Red flags” are clinical indicators of an acute crisis. When these are present, the priority shifts from long-term recovery to immediate safety stabilization.

• Suicidal or Homicidal Ideation: Any presence of a specific plan, intent, or preparatory behavior (e.g., giving away possessions or acquiring means) requires an emergency referral or hospitalization.
• Psychotic Features: The presence of delusions (fixed false beliefs) or hallucinations—particularly “command hallucinations”—marks a level of severity that standard antidepressant monotherapy rarely addresses.
• Severe Self-Neglect: When a patient stops eating, drinking, or maintaining basic hygiene to the point of physical danger, outpatient care is no longer sufficient.
• Manic “Switching”: If a patient begins exhibiting pressured speech, extreme impulsivity, or a decreased need for sleep, they may be experiencing a manic episode triggered by medication, suggesting a Bipolar Disorder diagnosis rather than MDD.

2. When to Refer: Beyond the Crisis

Not every referral is an emergency. Often, a referral is a strategic move to ensure the patient receives specialized tools that a generalist may not provide. The APA guidelines suggest referring to a psychiatrist or specialized psychologist in the following scenarios:

• The Rule of Treatment Resistance: One of the most common reasons for referral is Treatment-Resistant Depression (TRD). If a patient has failed to show a significant clinical response after two adequate trials of different evidence-based treatments (such as two different SSRIs or a combination of medication and CBT), a specialist should evaluate the patient for “adjunctive” therapies or more intensive interventions.
• Complexity and Comorbidity: Depression rarely travels alone. Referrals should be considered when MDD is complicated by:
• Co-occurring Disorders: Substance use disorders, eating disorders, or personality disorders that “muddy” the diagnostic picture.
• Diagnostic Ambiguity: When it is difficult to distinguish MDD from other conditions like Schizoaffective Disorder or complex PTSD.

Resources for Major Depressive Disorder

Crisis Support & Hotlines

• National Suicide Prevention Lifeline: Call or text 988 (available 24/7 in the United States)
• Crisis Text Line: Text “HELLO” to 741741 for free, 24/7 crisis support
• International Association for Suicide Prevention: https://www.iasp.info/resources/Crisis_Centres/ – Directory of crisis centers worldwide

NOTE: If you’re experiencing a mental health emergency, call 988 (US), go to your nearest emergency room, or contact emergency services in your country immediately.

References

American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text rev.).  https://doi.org/10.1176/appi.books.9780890425787

American Psychological Association. (2019). Clinical practice guideline for the treatment of depression across three age cohorts. https://www.apa.org/depression-guideline/guideline.pdf

Bains, N., & Abdijadid, S. (2020). Major depressive disorder. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; https://www.ncbi.nlm.nih.gov/books/NBK559078

De Menezes Galvão, A. C., Almeida, R. N., de Sousa, G. M., Jr, Leocadio-Miguel, M. A., Palhano-Fontes, F., de Araujo, D. B., Lobão-Soares, B., Maia-de-Oliveira, J. P., Nunes, E. A., Hallak, J. E. C., Schuch, F. B., Sarris, J., & Galvão-Coelho, N. L. (2021). Pathophysiology of Major Depression by Clinical Stages. Frontiers in psychology, 12, 641779. https://doi.org/10.3389/fpsyg.2021.641779

Mehra, A., Khanna, J., Singh, G., Sachdeva, V., & Bedi, N. (2025). A Comprehensive Review on Major Depressive Disorder: Exploring Etiology, Pathogenesis and Clinical Approaches. Current Behavioral Neuroscience Reports, 12(1), 18. https://doi.org/10.1007/s40473-025-00308-y

National Institute for Health and Care Excellence (NICE). (2022). Depression in adults: treatment and management. National Institute for Health and Care Excellence (NICE). https://www.ncbi.nlm.nih.gov/books/NBK583074/

Zhao, L., Lou, Y., Tao, Y., Wang, H., & Xu, N. (2025). Global, regional and national burden of depressive disorders in adolescents and young adults, 1990-2021: systematic analysis of the global burden of disease study 2021. Frontiers in public health, 13, 1599602. https://doi.org/10.3389/fpubh.2025.1599602