ICD-116A70	SINGLE EPISODE DEPRESSIVE DISORDER Single episode depressive disorder
ICD-10F32	Depressive episode
DSM-5-TRF32.x	Major Depressive Disorder, Single Episode

1. Definition and nosology

Single episode depressive disorder (ICD-11: 6A70 Single Episode Depressive Disorder; DSM-5-TR: Major Depressive Disorder, Single Episode — F32.x) — an affective disorder causing functional impairment, accompanied by significant cognitive, somatic, and psychomotor symptoms along with depressed mood and/or anhedonia for at least two weeks. In the patient's history only one major depressive episode is observed (in case of recurrence, code 6A71).

2. History

• Hippocrates (5th–4th centuries BC) — the term “melancholia”.
• Kraepelin (1899) — Depressive episode within manic-depressive insanity.
• DSM-III (1980) — official diagnosis “Major Depressive Disorder”; separation from bipolar disorder.
• DSM-5 (2013) — The “bereavement exclusion” has been removed — a major depressive episode can be diagnosed in a patient even after the loss of a loved one.
• ICD-11 (2019) — Single episode (6A70) and Recurrent (6A71) are coded separately.

3. Epidemiology

• Lifetime prevalence: 15–20% (Kessler R.C. NESARC-III, Hasin D.S. et al. JAMA Psychiatry 2018).
• Annual prevalence: ~6–8%.
• Sex: 1.5–2 times higher in females.
• Onset: mid-20s to 30 years; but possible at any age.
• Suicide: depressive disorder associated with ~50% of suicide deaths.
• Comorbidity: anxiety disorders 60%, substance use 25%, pain, cardiovascular, diabetes.
• Mortality: overall mortality increased 1.5 times (cardiovascular, suicide).

4. Aetiology and pathogenesis

• Heritability 35–40% (Sullivan P.F. et al. Am J Psychiatry 2000 meta-analysis); less than bipolar.
• GWAS — 100+ risk loci (Howard D.M. et al. Nat Neurosci 2019, n>800,000).
• Neurobiological — monoaminergic (serotonin, norepinephrine, dopamine) hypothesis; HPA axis dysregulation, elevated cortisol; hippocampal volume reduction; inflammatory hypothesis (CRP, IL-6).
• Risk factors: childhood trauma, family history, acute stress, chronic medical illness, social isolation, substance use, postpartum period, hypothyroidism.

5. Clinical features

5.1 Core symptoms (DSM-5-TR — ≥ 5 symptoms × 2 weeks, at least 1 of which is 1 or 2)

1. Persistent low mood.
2. Anhedonia — loss of interest and pleasure.
3. Weight or appetite changes.
4. Sleep disturbance (insomnia or hypersomnia).
5. Psychomotor agitation or retardation (observable by others).
6. Fatigue or loss of energy.
7. Worthlessness or excessive guilt.
8. Difficulty concentrating and impaired decision-making.
9. Suicidal thoughts or plan.

5.2 Qualifiers (DSM-5-TR)

• Severity: mild, moderate, severe.
• With psychotic features (delusion or hallucination).
• Atypical features (hypersomnia, hyperphagia, leaden paralysis).
• Melancholic features.
• Catatonic features.
• Peripartum onset.
• Seasonal pattern.
• Mixed features (manic components).
• With anxiety.

6. Diagnosis

6.1 Unified diagnostic criteria (DSM-5-TR · ICD-11 consensus points)

A. The presence of 5 or more symptoms for ≥ 2 weeks; at least one of which must be depressed mood or anhedonia.

B. Significant distress or functional impairment.

C. Exclusion of substance or medical condition.

D. Never had a manic or hypomanic episode.

6.2 Source-specific clarifications

• DSM-5-TR: “Bereavement exclusion” removed (in DSM-IV, diagnosis was not made during 2 months of bereavement); grief and depressive episode can co-occur.
• ICD-11 (6A70): single episode separately coded; severity and psychotic feature qualifiers.
• NICE NG222 (2022): Severity classification: mild, severe (instead of mild/moderate/severe in DSM); treatment algorithms based on severity.

6.3 Diagnostic algorithm

1. Clinical interview.
2. Structured interview (SCID-5, MINI).
3. Scales - PHQ-9 (screening and monitoring), HAM-D, MADRS, BDI-II.
4. Suicide risk (C-SSRS).
5. Bipolar screening (MDQ, HCL-32) — to rule out bipolar episodes.
6. Medical and laboratory (thyroid, B12, folate, ferritin, liver, kidney, pregnancy) — to exclude somatic causes.
7. Toxicology screening (suspect substance use).

6.4 Differential diagnosis

7. Examination and assessment

• PHQ-9 — standard in primary care; ≥10 score indicates moderate-severe depression.
• HAM-D-17 (Hamilton), MADRS — clinical and research.
• BDI-II — self-assessment.
• C-SSRS — suicide risk.
• Laboratory: complete blood count, thyroid, B12, folate, ferritin, liver/kidney, glucose.
• EKG — before starting TCA or QT-prolonging medications.

8. Treatment

8.1 General Principles (NICE NG222 · APA 2010 · CANMAT 2016 Consensus)

1. Stepwise approach based on severity:
   • Mild (PHQ-9 5–9) — guided self-help, CBT-based internet interventions, physical activity, observation.
   • Moderate (PHQ-9 10–14) — CBT or IPT, or pharmacotherapy (SSRI); patient choice.
   • Moderately severe (PHQ-9 15–19) — pharmacotherapy (SSRI) or a high-intensity psychological intervention; combination preferred.
   • Severe (PHQ-9 ≥ 20 or psychotic features) — combination of pharmacotherapy + psychotherapy; severe psychotic/suicidal risk — inpatient admission and ECT.
2. First-line pharmacotherapy: SSRIs — sertraline, escitalopram, fluoxetine, paroxetine, citalopram. Effect in 4–6 weeks; titration required.
3. SNRI — venlafaxine, duloxetine — alternative or comorbid pain/anxiety.
4. Other — mirtazapine (sleep and appetite problems), bupropion (few sexual side effects, ADHD comorbid), agomelatine, vortioxetine (cognitive component).
5. Refractory: SSRI + lithium or quetiapine or aripiprazole; SSRI combinations; ketamine/esketamine (intranasal — FDA approved 2019, severe refractory); ECT.
6. Psychotherapy first line alternative — monotherapy in mild-to-moderate depression, combination with pharmacotherapy in severe cases; specific methods and evidence base in the “Treatment methods” list (CBT, IPT, behavioral activation, MBCT).
7. Suicide risk management — Active assessment; hospitalization if risk high; restricted access to means (weapons, medications); psychosocial support.
8. Treatment duration: first episode: continuation after remission for 6–12 months; long-term in case of relapse.

8.2 Pharmacotherapy

8.3 Source-Specific Clarifications

• NICE NG222 (2022): stepwise algorithm based on severity; “less severe” — CBT or guided self-help first-line; “more severe” — combination.
• APA Practice Guideline (2010, 2019 update): SSRI first-line; CBT / IPT first-line alternative.
• CANMAT 2016: A 4-step algorithm based on severity and incident.
• Cipriani A. et al. Lancet 2018 network meta-analysis: Comparison of 21 antidepressants — agomelatine and amitriptyline highest efficacy; fluoxetine, fluvoxamine, reboxetine and trazodone lowest. The most acceptable were agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine; reboxetine ranked among the worst on both efficacy and acceptability. Efficacy differences are clinically modest.

Treatment methods

1. CBT for depression — Beck (Beck A.) — Cognitive restructuring, behavioral activation; 12–20 sessions. Evidence: Cuijpers P. et al. Cochrane meta-analyses — medium effect, comparable to pharmacotherapy; combination superior to monotherapy in severe cases.
2. Interpersonal Therapy (IPT — Interpersonal Therapy) — Klerman (Klerman G.), Weissman (Weissman M.) — 4 problem areas – grief, role transition, role conflict, interpersonal deficit. 12–16 sessions. RCT evidence comparable to CBT.
3. Behavioral Activation — Jacobson N., Martell C. — Systematic increase of positive activities, reduction of avoidance. Dimidjian S. et al. J Consult Clin Psychol 2006 RCT — comparable effect to CBT.
4. Mindfulness-Based Cognitive Therapy (MBCT) — Segal Z., Williams M., Teasdale J — In relapse prevention; particularly if history of ≥3 episodes, effect may be superior to antidepressant continuation (Kuyken W. et al. Lancet 2015).
5. Patient Health Questionnaire-9 (PHQ-9) — Kroenke (Kroenke K.), Spitzer (Spitzer R.L.) — Gold standard screening and monitoring tool in primary medical care.
6. HAM-D / MADRS — Clinician-rated depressive severity scales.
7. ECT — Severe psychotic depression, refractory, suicide risk, food intake disorder, pregnancy. UK ECT Review Group Lancet 2003 — ECT superior to pharmacotherapy in severe cases.
8. Esketamine / Ketamine — FDA 2019 intranasal esketamine (Spravato) for severe refractory depression; rapid antidepressant effect (hours-days); administration under clinic supervision. Daly E.J. et al. JAMA Psychiatry 2018.
9. Repetitive Transcranial Magnetic Stimulation (rTMS — repetitive Transcranial Magnetic Stimulation) — FDA-approved (2008) for refractory depression; 4–6 week course, target left DLPFC.

9. Prognosis

• Spontaneous remission occurs in 50% within one year (though most remissions occur without antidepressant treatment); relapse risk is high.
• The risk of a subsequent episode increases after each episode.
• Suicide risk is particularly high in the first weeks.
• Monitoring — PHQ-9 / MADRS, suicide risk, side effects, compliance; more frequent in first 12 weeks.
• Duration of treatment — 6–12 months after remission in first episode.

10. Myths and misconceptions

Myth 1: “Depression is just ‘sadness’; it can be overcome voluntarily”

Evidence: Depression is a complex neurobiological disorder involving HPA axis dysregulation, monoamine imbalance, and structural changes (e.g., hippocampus); it is not volitionally controllable. The APA, WHO, and NICE define it as a medical condition.

Myth 2: “Antidepressants are addictive”

Evidence: SSRI and SNRI do not cause addiction — no abuse or tolerance. But a discontinuation syndrome does exist (especially with the short half-life of paroxetine, venlafaxine) — this is not addiction, but physiological adaptation; it resolves with gradual discontinuation.

Myth 3: “Antidepressant changes the patient's personality”

Evidence: Antidepressants reduce the symptoms; they do not change the personality. If a patient says that he or she no longer feels like themselves, that is a side effect — emotional blunting — and the answer is to change the drug or lower the dose.

Myth 4: “Antidepressants are no better than placebo”

Evidence: Cipriani Lancet 2018 — 21 antidepressants significantly superior to placebo; but effect is modest, especially in mild depression. In moderate-severe depression, the effect is clinically significant.

Myth 5: “Diet (omega-3, B vitamins, magnesium) replaces antidepressants”

Evidence: Some supplements (omega-3, vitamin D in deficiency) may have mild adjunct effect, but do not replace main treatment in moderate-severe depression. SMILES study (Jacka F.N. BMC Med 2017) — Mediterranean-type diet as mild adjunct.

Myth 6: “St John's Wort is a natural antidepressant and can replace antidepressants”

Evidence: St John's wort shows efficacy in mild depression (Cochrane Linde K. 2008), but the evidence base is limited in moderate-to-severe depression; due to CYP induction, it reduces the levels of numerous drugs (contraceptives, anticoagulants, antidepressants, antiretrovirals) — a serious interaction.

Myth 7: Only exercise or psychotherapy is sufficient; medication is unnecessary

Evidence: In mild depression, psychotherapy and exercise may sometimes be sufficient, but in moderate-to-severe depression and particularly when suicidal risk is present, pharmacotherapy is necessary; NICE NG222 and APA 2010.

Myth 8: ECT is an outdated or traumatic treatment

Evidence: modern ECT (under anesthesia, with muscle relaxants) is safe and highly effective; it is the gold standard for severe refractory and psychotic depression. UK ECT Review Group Lancet 2003.

Myth 9: Antidepressants cause suicide

Evidence: FDA black box in children and adolescents (especially first weeks) increased risk of suicidal thoughts — requires monitoring of these clinics, but long-term antidepressants reduce suicide risk (Stone M. et al. BMJ 2009).

Myth 10: “Depression cannot be diagnosed during the grieving period”

Evidence: DSM-5 eliminated the bereavement exclusion; grief and major depressive episode can co-occur; pathological forms of grief (prolonged grief disorder — 6B43) are separate.

Myth 11: “Depression in healthy patients is a marker of psychological ‘weakness’”

Evidence: Depression can occur in any individual; the concept of “psychological strength” is stigmatizing and incorrect; it should be evaluated as a medical condition.

11. Sources

1. WHO. ICD-11. 6A70 Single episode depressive disorder. 2024.
2. APA. DSM-5-TR. 2022.
3. NICE NG222. Depression in adults: treatment and management. 2022.
4. APA. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010.
5. Kennedy S.H., Lam R.W., McIntyre R.S. et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder. Can J Psychiatry 2016;61(9):540–560.
6. Cipriani A., Furukawa T.A., Salanti G. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018;391(10128):1357–1366.
7. Hasin D.S., Sarvet A.L., Meyers J.L. et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry 2018;75(4):336–346.
8. Howard D.M. et al. Genome-wide meta-analysis of depression identifies 102 independent variants. Nat Neurosci 2019;22(3):343–352.
9. Cuijpers P., Karyotaki E., de Wit L., Ebert D.D. The effects of fifteen evidence-supported therapies for adult depression: A meta-analytic review. Psychother Res 2020;30(3):279–293.
10. Kuyken W., Hayes R., Barrett B. et al. Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse. Lancet 2015;386(9988):63–73.
11. Kroenke K., Spitzer R.L., Williams J.B. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16(9):606–613.
12. Daly E.J. et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression. JAMA Psychiatry 2018;75(2):139–148.
13. Jacka F.N. et al. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Med 2017;15(1):23.
14. UK ECT Review Group. Lancet 2003;361(9360):799–808.
15. Stone M., Laughren T., Jones M.L. et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009;339:b2880.
16. Beck A.T., Rush A.J., Shaw B.F., Emery G. Cognitive Therapy of Depression. New York: Guilford Press, 1979.
17. Martell C.R., Dimidjian S., Herman-Dunn R. Behavioral Activation for Depression: A Clinician’s Guide. New York: Guilford Press, 2010.
18. Weissman M.M., Markowitz J.C., Klerman G.L. Comprehensive Guide to Interpersonal Psychotherapy. New York: Basic Books, 2000.
19. Segal Z.V., Williams J.M.G., Teasdale J.D. Mindfulness-Based Cognitive Therapy for Depression. 2nd ed. New York: Guilford Press, 2013.
20. Jacobson N.S., Dobson K.S., Truax P.A. et al. A component analysis of cognitive-behavioral treatment for depression. J Consult Clin Psychol 1996;64(2):295–304.