Major Depressive Disorder: An Evidence-Based Guide to Diagnosis, Mechanisms, and Treatment

Key points

Depression affects roughly 280 million people worldwide and ~5% of adults at any time; it is a leading cause of disability. (Organisation mondiale de la santé)
Diagnosis is clinical (DSM-5-TR/ICD-11), aided by validated screeners (e.g., PHQ-9) and careful differential to rule out bipolar disorder, medical mimics, and substance effects. (CNIB, Iris, Jacobimed)
First-line treatments include evidence-based psychotherapies (CBT, IPT, BA, etc.) and antidepressant medications (SSRIs/SNRIs and others); combined therapy often yields the best acute outcomes in moderate–severe depression. (PubMed, The Lancet)
For treatment-resistant depression (TRD), options with proven benefit include augmentation (e.g., aripiprazole), rTMS, ECT, and esketamine in carefully selected patients. (PMC, acpjournals.org)
Maintenance strategies (continued pharmacotherapy and/or relapse-prevention psychotherapy such as MBCT) significantly reduce recurrence. (ScienceDirect, JAMA Network)

Epidemiology and burden

Depression is common across countries and life stages. The World Health Organization estimates ~280 million people have depression (≈3.8% overall; ≈5% of adults, higher in women). Beyond prevalence, depressive disorders account for a substantial share of years lived with disability and global DALYs. (Organisation mondiale de la santé, PubMed)

Diagnostic framework

DSM-5-TR and ICD-11

Major depressive disorder is defined by at least 5 symptoms during the same 2-week period, including depressed mood and/or anhedonia, with distress/impairment and not better explained by substances or medical conditions. DSM-5-TR also specifies specifiers (e.g., anxious distress, melancholic features). ICD-11 provides harmonized criteria and updated severity guidance. (CNIB, Iris)

Screening and case-finding

In primary care and general medical settings, the PHQ-9 is a validated, self-administered instrument aligned with DSM criteria; it supports severity assessment and monitoring. The USPSTF (2023) recommends screening all adults, including perinatal populations, when adequate systems are in place for diagnosis, treatment, and follow-up. Screening alone is not diagnostic and should always be paired with clinical evaluation. (Jacobimed, uspreventiveservicestaskforce.org)

Differential diagnosis and common comorbidities

Key differentials include bipolar depression (screen for past mania/hypomania), substance-/medication-induced mood disorder (e.g., steroids, isotretinoin), neurocognitive disorders in older adults, hypothyroidism, anemia, sleep apnea, and grief. Comorbid anxiety disorders, PTSD, and substance use disorders are frequent and influence treatment sequencing. (See DSM-5-TR/ICD-11 overviews.) (CNIB, Iris)

Pathophysiology: what we know (and don’t)

Contemporary models integrate monoaminergic dysfunction, stress-system (HPA) dysregulation, neuroplasticity/BDNF changes, and immune-inflammatory signaling, with convergent evidence from neuroimaging showing network-level alterations (e.g., default mode and salience networks). These mechanisms are heterogeneous and likely define subtypes with differential treatment response—an area of active research. (PMC, ScienceDirect)

Evidence-based treatments

Psychotherapies

A 2021 network meta-analysis across the main therapies for adult depression concluded that several modalities—CBT, interpersonal psychotherapy (IPT), behavioral activation (BA), problem-solving therapy, psychodynamic therapy, and third-wave approaches—are efficacious and acceptable in acute treatment, with modest differences among them. Choice should be guided by patient preference, availability, prior response, and comorbidities. (PubMed, Wiley Online Library)

Combined treatment (psychotherapy + pharmacotherapy) provides superior acute outcomes versus either alone in many moderate–severe cases. (PubMed)

Relapse prevention. For recurrent MDD, mindfulness-based cognitive therapy (MBCT) reduces relapse risk versus usual care and performs comparably to maintenance antidepressants in selected cohorts; benefits are larger in those with residual symptoms. (JAMA Network, The Lancet)

Pharmacotherapy

The 2018 Lancet network meta-analysis (522 RCTs; 116,477 participants) showed all 21 commonly used antidepressants outperformed placebo in acute MDD; between-drug differences exist but are modest at the group level. Tolerability/acceptability varies and should inform shared decision-making. (The Lancet, PubMed)

First-line choices (per major guidelines such as NICE/APA) typically include SSRIs (e.g., sertraline, escitalopram), SNRIs (e.g., venlafaxine, duloxetine), bupropion, mirtazapine, and vortioxetine. Start low, titrate to a therapeutic dose, and reassess at 4–6 weeks; continue for at least 6–12 months after remission before considering taper, longer for recurrent or chronic depression. (PubMed, apa.org)

Treatment sequencing and STAR*D insights. The large pragmatic STAR*D program found cumulative remission rates increase with sequential steps, but probabilities fall with each switch/augmentation; residual symptoms predict relapse—underscoring the importance of achieving and sustaining remission. (PubMed)

Augmentation and TRD. For inadequate response after an adequate trial:

Atypical antipsychotic augmentation (e.g., aripiprazole, quetiapine extended-release) improves response/remission in TRD, with metabolic and akathisia risks to monitor. (PMC)
Other evidence-based options include lithium or thyroid hormone augmentation in selected patients. (See guideline summaries.) (PubMed)

Esketamine (intranasal) is approved for TRD and for depressive symptoms with acute suicidal ideation/behavior in combination with an oral antidepressant. Systematic reviews indicate modest, rapid-onset efficacy with dissociation and blood-pressure elevations as notable adverse effects; use requires Risk Evaluation and Mitigation strategies and clinic monitoring. (PMC)

Somatic treatments

Repetitive transcranial magnetic stimulation (rTMS): Multiple meta-analyses and guideline updates support rTMS for MDD after antidepressant nonresponse; it is noninvasive with favorable tolerability. Protocols include high-frequency left-DLPFC and intermittent theta-burst stimulation. (PMC)
Electroconvulsive therapy (ECT): Remains the most rapid and effective acute treatment for severe or psychotic depression, high suicide risk, or life-threatening conditions (e.g., refusal to eat). Modern ECT is safe under anesthesia with cognitive side effects that are usually transient; a 2022 NEJM review summarizes indications, techniques, and outcomes. (acpjournals.org)

Special populations and clinical nuances

Perinatal depression: Screen during pregnancy and postpartum; psychotherapy is first-line for mild–moderate cases. When medication is indicated, SSRIs (e.g., sertraline) have the largest safety database; shared decision-making and obstetric collaboration are essential. (See APA/NICE guidance.) (apa.org, PubMed)
Late-life depression: Presentations may be more somatic or cognitive; prioritize ruling out vascular, neurodegenerative, and metabolic contributors. ECT and rTMS are often well-tolerated and effective when medication fails. (PMC)
Comorbid medical illness: Consider drug–disease and drug–drug interactions (e.g., anticoagulants with SSRIs, hyponatremia risk in older adults).

Relapse prevention and maintenance care

Relapse is common after response. Evidence supports:

Maintenance antidepressants (at the dose that achieved remission) for ≥6–12 months after a first episode and ≥2 years (or indefinitely) in recurrent depression, individualized to risk. (apa.org)
Sequential or maintenance psychotherapy (e.g., MBCT, continuation CBT/IPT) to reduce recurrence, especially in recurrent MDD or residual symptoms. (JAMA Network)
Systematic follow-up with measurement-based care (e.g., PHQ-9 tracking) and early intervention on residual symptoms or side effects. (Jacobimed)

Practical, stepped-care algorithm (evidence-aligned)

Identify & assess. Screen with PHQ-9; assess suicide risk, bipolarity, substances, and medical mimics. Classify severity and specifiers (DSM-5-TR/ICD-11). (Jacobimed, Iris)
Mild depression. Offer low-intensity interventions and/or structured psychotherapy (CBT/BA/IPT); consider watchful waiting with close follow-up when appropriate. (PubMed)
Moderate–severe or functional impairment. Start an SSRI/SNRI/bupropion/mirtazapine and evidence-based psychotherapy when feasible. Reassess at 4–6 weeks; optimize dose. (The Lancet)
Nonresponse after adequate trial. Switch class or augment (e.g., aripiprazole; lithium/thyroid in select cases). If multiple failures, consider rTMS, ECT, or esketamine per indication and availability. (PMC, acpjournals.org)
After remission. Continue treatment for relapse prevention; consider MBCT/CBT maintenance strategies; taper slowly with monitoring when appropriate. (JAMA Network)

Safety notes (for readers)

Acute suicidality, psychotic features, catatonia, severe dehydration/malnutrition, or failure to care for self are emergencies requiring urgent specialist assessment; ECT is often indicated. (acpjournals.org)
Antidepressants carry boxed warnings for increased suicidal thinking in young adults; monitor closely during initiation and dose changes. (See guideline summaries.) (apa.org)

Selected references (evidence and guidelines)

World Health Organization. Depressive disorder (depression) – fact sheet (prevalence, burden). (Organisation mondiale de la santé)
WHO. ICD-11: Clinical descriptions and diagnostic requirements (2024)—depressive episode and related disorders. (Iris)
StatPearls (NCBI Bookshelf). Major Depressive Disorder—DSM-aligned diagnostic overview. (CNIB)
USPSTF (2023) Depression Screening—Recommendation and evidence report (JAMA). (uspreventiveservicestaskforce.org)
Kroenke et al. PHQ-9 validation (J Gen Intern Med, 2001). (Jacobimed)
NICE Guideline: Depression in adults (2022, updates)—diagnosis and management. (PubMed)
APA Practice Guideline for MDD (2023)—assessment and treatment recommendations. (apa.org)
Cipriani et al. Network meta-analysis of 21 antidepressants (The Lancet, 2018). (The Lancet)
Cuijpers et al. Network meta-analysis of psychotherapies (World Psychiatry, 2021). (PubMed)
STAR*D program—sequential treatment outcomes. (PubMed)
Esketamine for TRD—systematic review/meta-analysis (Am J Psychiatry, 2024). (PMC)
rTMS for MDD—updated evidence and indications (BMC Psychiatry meta-analyses, 2023). (PMC)
Electroconvulsive Therapy—comprehensive NEJM review (2022). (acpjournals.org)
Maintenance/relapse prevention: MBCT individual-patient meta-analysis (JAMA Psychiatry, 2016). (JAMA Network)

Attribution and disclaimer

This article is informational and does not replace individualized clinical care. If you or a reader is experiencing suicidal thoughts or a mental-health crisis, seek emergency help immediately.

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