Depression

Overview & Definition

Depression (major depressive disorder, MDD) is a common, relapsing-remitting mood disorder characterised by a persistent lowering of mood and a pervasive loss of interest or pleasure, accompanied by disturbances in sleep, appetite, energy, concentration, self-worth, and psychomotor activity, severe enough to cause functional impairment. It is the leading cause of disability worldwide (Global Burden of Disease) and carries a substantially elevated risk of suicide. ^[1]

The cardinal diagnostic threshold (DSM-5 / ICD-11) requires 5 or more of nine specified symptoms present during the same 2-week period, representing a change from previous functioning, with at least one symptom being either (a) depressed mood or (b) anhedonia (loss of interest or pleasure). Symptoms must be present most of the day, nearly every day. Crucially, the episode must cause clinically significant distress or impairment and must not be better explained by a medical condition, substance, or another psychiatric disorder (notably, no prior manic/hypomanic episode — which would reclassify the diagnosis as bipolar disorder).^[1]

Depression sits within the broader category of mood (affective) disorders, distinguished from bipolar disorders by the absence of any manic or hypomanic episode, and from persistent depressive disorder (dysthymia) by its episodic, more severe but less chronic course (a major depressive episode requires a minimum duration of 2 weeks, whereas dysthymia requires a depressed mood on more days than not for at least 2 years). ^[1]

Classification

Depression is classified along several axes: (1) by severity (mild, moderate, severe — with or without psychotic features), (2) by course (single episode vs recurrent, with or without inter-episode recovery), (3) by clinical specifier (melancholic, atypical, psychotic, catatonic, peripartum-onset, seasonal pattern, with mixed features, with anxious distress), and (4) by aetiology (primary/unipolar vs secondary to a general medical condition or substance). ^[1]

Within DSM-5, depression-related diagnoses include major depressive disorder (single or recurrent episode), persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder (children, severe temper outbursts), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, and depressive disorder due to another medical condition. ICD-11 uses a related structure with "single episode depressive disorder" and "recurrent depressive disorder" as distinct entities. ^[1]

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The mnemonic SIGECAPS encodes all nine criterion symptoms; depressed mood itself is added separately (Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicide — plus Mood). For a diagnosis, 5 or more must be present for 2 or more weeks, including depressed mood or anhedonia. ^[1]

Epidemiology & Risk Factors

• Prevalence: Lifetime prevalence approximately 15 to 17 percent; 12-month point prevalence around 5 to 7 percent. More than 300 million people affected worldwide (WHO).
• Sex: Females affected twice as often as males (2:1); the sex difference emerges at puberty and narrows after menopause.
• Age: Mean age of onset is the late teens to mid-20s (median about 25 years), but it may present at any age.
• Recurrence: Highly recurrent — after one episode the relapse risk is about 50 percent, after two episodes about 70 percent, and after three episodes approximately 90 percent.
• Socioeconomic: Higher rates with unemployment, low income, social isolation, urban dwelling, and chronic stress.
• Genetic risk factors: Heritability approximately 35 to 40 percent (twin studies). First-degree relatives have a 2- to 3-fold increased risk. The polygenic contribution involves many loci of small effect (no single "depression gene"); serotonin-transporter-linked polymorphic region (5-HTTLPR) interaction with stress is the classic gene-environment example.
• Psychosocial risk factors: Adverse childhood experiences (abuse, neglect, parental loss), recent stressful life events (loss, humiliation, entrapment), chronic interpersonal difficulty, low social support, domestic violence, and bereavement.
• Medical associations: Chronic pain, cardiovascular disease, stroke, Parkinson's disease, multiple sclerosis, cancer, hypothyroidism, chronic kidney disease, HIV, dementia, diabetes, and the postpartum period.
• Substance use: Alcohol misuse, benzodiazepine dependence, stimulant use and withdrawal, and opioid misuse all elevate risk. ^[1]

Pathophysiology

No single mechanism explains depression; current models integrate monoamine neurochemistry, neuroendocrine stress systems, neuroplasticity, inflammation, and psychosocial stress. ^[1]

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1. Monoamine hypothesis (the classic pharmacological model). Depression is associated with functional deficiency of the monoamine neurotransmitters serotonin (5-HT) and noradrenaline, and to a lesser degree dopamine, in central synapses. Reserpine (depletes monoamines) and methyldopa precipitated depression, while drugs that increase synaptic monoamines (TCAs, MAOIs, SSRIs) relieve it. The therapeutic delay of antidepressants (weeks) despite immediate monoamine elevation showed the model is incomplete — downstream receptor down-regulation (e.g., presynaptic 5-HT1A autoreceptor desensitisation) and adaptive neuroplastic changes are required for clinical effect. ^[1]

2. Neuroendocrine — HPA axis dysregulation. Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis, producing hypercortisolaemia. Roughly half of depressed patients fail to suppress cortisol on the dexamethasone suppression test (non-suppression correlates with melancholic/psychotic depression and predicts relapse). Sustained cortisol is neurotoxic to the hippocampus. ^[1]

3. Neurotrophin and neuroplasticity hypothesis. Brain-derived neurotrophic factor (BDNF) is reduced in the hippocampus and prefrontal cortex in depression and is normalised by antidepressant treatment, ECT, exercise, and repeated ketamine. Stress reduces hippocampal BDNF and impairs neurogenesis; antidepressants promote hippocampal neurogenesis over weeks — a candidate mechanism for the therapeutic lag. Volume loss of the hippocampus (8 to 10 percent reduction) and the subgenual anterior cingulate cortex is seen in recurrent depression. ^[1]

4. Neuroinflammation / cytokine hypothesis. About one-third of depressed patients show raised inflammatory markers (C-reactive protein, interleukin-6, tumour necrosis factor-alpha). Administration of interferon-alpha or interleukin-2 induces depression-like symptoms (sickness behaviour: anhedonia, fatigue, anorexia, sleep disturbance), supporting a cytokine-driven phenotype (especially with somatic symptoms and treatment resistance). ^[1]

5. Glutamate and rapid-acting model. Dysfunction of the glutamatergic system underlies the rapid antidepressant effect of ketamine (NMDA-receptor antagonist), which produces improvement within hours via synaptogenesis and BDNF/mTOR signalling — distinct from the monoamine delay. ^[1]

6. Cognitive and psychological models. Beck's cognitive triad describes negative views of the self, the world, and the future; automatic negative thoughts and cognitive distortions (overgeneralisation, catastrophising) are causal and modifiable by cognitive behavioural therapy. Learned helplessness (Seligman), arising from uncontrollable stress, parallels the motivational deficit of depression. ^[1]

7. Sleep architecture. Depression shortens sleep-onset latency, reduces slow-wave (stage N3) sleep, brings REM latency forward (shortened), and increases REM density — biological markers that normalise with recovery and ECT. ^[1]

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Clinical Presentation

The presentation is heterogeneous. The core features are depressed mood and anhedonia; surrounding symptoms cluster into emotional, cognitive, behavioural, somatic, and vegetative domains. Symptoms must be present most of the day, nearly every day for at least 2 weeks and represent a change from baseline. ^[1]

• Mood: Pervasive sadness, emptiness, "feeling flat", hopelessness, tearfulness, irritability (especially in adolescents, men, and the elderly). Children may present with irritability rather than sadness.
• Anhedonia: Loss of interest or pleasure in usually enjoyable activities; reduced reactivity.
• Cognition: Poor concentration, slowed thinking (bradyphrenia), indecisiveness, rumination, impaired short-term memory, negative cognitive triad, excessive or delusional guilt, suicidal ideation.
• Vegetative/somatic: Insomnia (early, middle, or terminal — early-morning wakening in melancholic depression) or hypersomnia; appetite/weight loss or gain; fatigue, loss of energy; loss of libido; constipation; generalised aches.
• Psychomotor: Retardation (slowed movement and speech, reduced facial expressiveness) or agitation (pacing, hand-wringing).
• Thought content: Worthlessness, hopelessness, helplessness, preoccupation with death, recurrent suicidal ideation, and (in psychotic depression) nihilistic, hypochondriacal, or persecutory delusions (mood-congruent). ^[1]

Atypical presentations

• Elderly: Often presents with somatic complaints, cognitive impairment ("pseudodementia"), agitation, somatic delusions, or unexplained pain rather than reporting sadness. Multiple physical complaints, weight loss, and refusal to eat may dominate. Suicide risk is high (especially elderly men). Onset after age 60 ("vascular depression") is associated with white-matter changes and executive dysfunction.
• Adolescents: Irritability, academic decline, school refusal, social withdrawal, conduct disturbance, self-harm, eating change, substance use — rather than verbalised depressed mood. Sleep and appetite may increase.
• Children: Somatic complaints (headaches, abdominal pain), school refusal, separation anxiety, behavioural regression, decline in school performance.
• Pregnancy and postpartum: Peripartum onset (within 4 weeks of delivery per DSM; clinically often up to 12 months). May include thoughts of harming the infant — must be asked about directly.
• Men: May present with anger, irritability, substance use, risk-taking, or work underperformance rather than acknowledged sadness; higher completed-suicide rate.
• Medically ill / immunocompromised: Symptoms overlap with the underlying disease (fatigue, anorexia, weight loss); assess anhedonia, guilt, hopelessness, and suicidal ideation, which are more specific to depression.
• Cultural: Some cultures emphasise somatic ("nerves", weakness, body heat) rather than affective complaints; culture-bound idioms must be elicited. ^[1]

Differential Diagnosis

A broad differential must be excluded because organic causes are reversible and antidepressants can be harmful if misdiagnosed (e.g., precipitating mania in bipolar depression). At least three distinguishing features are given for each. ^[1]

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Clinical & Bedside Assessment

Diagnosis is clinical, based on history and mental state examination. A structured assessment covers the present episode, psychiatric and medical history, drug and alcohol use, family history, psychosocial context, and risk. ^[1]

Mental state examination (MSE) in depression

• Appearance/behaviour: Psychomotor retardation (slow movement, reduced gestures, stooped posture, poor eye contact) or agitation; poor self-care; tearfulness; sometimes unkempt.
• Speech: Slow, low volume, long latency (retardation) — may progress to mutism in severe/catatonic depression.
• Mood (subjective) and affect (objective): Subjectively low; objectively constricted, blunted, or flat. Mood may be reactive (atypical) or non-reactive (melancholic).
• Thought: Slow (bradyphrenia), rumination, hopelessness, worthlessness, helplessness, guilt, suicidal/homicidal ideation; in psychotic depression — delusions of guilt, ruin, nihilism (Cotard syndrome — belief one is dead or organs are rotting), hypochondriacal or persecutory delusions.
• Perception: Second-person auditory hallucinations (derogatory) in psychotic depression; often mood-congruent.
• Cognition: Impaired attention and concentration; short-term memory reduced (pseudodementia pattern in the elderly).
• Insight: Usually preserved early; may be impaired in severe or psychotic depression. ^[1]

Suicide risk assessment — mandatory at every contact

Use a structured framework (e.g., the Columbia Suicide Severity Rating Scale, C-SSRS). Assess: ^[1]

1. Ideation — passive (thoughts of being dead) vs active (thoughts of killing oneself); frequency, intensity, duration.
2. Plan — specificity, lethality, method chosen.
3. Intent — stated desire to act.
4. Means — access to firearms, medication (especially antidepressants — prescribe limited quantities; tricyclics are lethal in overdose), ligature points.
5. Preparatory acts — giving away possessions, writing a will, rehearsal, saying goodbye.
6. Protective factors — family/responsibilities, religious/moral objection, future plans, social support, engagement with treatment.
7. Risk factors — previous attempts (strongest predictor), male sex, older or adolescent age, living alone, unemployment, substance misuse, recent loss, chronic pain, hopelessness, psychotic depression, bipolar depression, access to lethal means. ^[1]

Risk stratification: any active plan plus intent plus means = high risk — do not leave alone; arrange urgent psychiatric assessment, consider admission, remove means, involve crisis team. Passive ideation without plan = lower risk but still arrange follow-up within 24 to 48 hours and a safety plan. ^[1]

Investigations

There is no biological test for depression. Investigations aim to exclude organic mimics, establish a baseline before psychotropic drugs, and screen for comorbidity. ^[1]

• Bloods: Full blood count (anaemia), urea and electrolytes (chronic kidney disease, hyponatraemia), liver function tests, thyroid-stimulating hormone (TSH) (hypothyroidism is the classic mimic), vitamin B12 and folate, 25-hydroxyvitamin D, fasting glucose/HbA1c, lipid profile, calcium (hyperparathyroidism), and consider HIV/syphilis serology where indicated.
• Baseline before drug treatment: Weight, height, BMI, blood pressure, pulse, and (before QT-prolonging drugs such as citalopram/escitalopram) an ECG in patients with cardiac disease, electrolyte disturbance, the elderly, or those on other QT-prolonging drugs.
• Substance screen: Urine drug screen and alcohol history (AUDIT / CAGE) where suspected.
• Neuroimaging (CT/MRI brain): Only if focal neurology, new-onset psychosis, cognitive impairment, late-onset depression (over 55) with atypical features, or before ECT.
• EEG: Not routine; to distinguish pseudodementia or atypical presentations. ^[1]

Validated rating scales (reproduced for examination use)

PHQ-9 (Patient Health Questionnaire-9) — self-report of the nine DSM criteria over the last 2 weeks (0 = not at all to 3 = nearly every day; maximum score 27). Question 9 screens for suicidality. ^[1]

• 1 to 4: minimal/none
• 5 to 9: mild
• 10 to 14: moderate
• 15 to 19: moderately severe
• 20 to 27: severe
• A score of 10 or more has a sensitivity and specificity of approximately 88 percent for major depression. A change of 5 points is the minimal clinically important difference. ^[1]

HAM-D / HDRS-17 (Hamilton Depression Rating Scale) — clinician-rated (maximum score 52): ^[1]

• 0 to 7: normal (no depression)
• 8 to 13: mild
• 14 to 18: moderate
• 19 to 22: severe
• 23 or more: very severe
• Response is defined as a 50 percent reduction from baseline; remission as a final score of 7 or less. ^[1]

MADRS (Montgomery-Asberg Depression Rating Scale) — clinician-rated, 10 items, sensitive to change (maximum score 60): ^[1]

• 0 to 6: normal/suspected
• 7 to 19: mild
• 20 to 34: moderate
• 35 to 60: severe ^[1]

BDI-II (Beck Depression Inventory-II) — self-report, 21 items (maximum score 63): ^[1]

• 0 to 13: minimal
• 14 to 19: mild
• 20 to 28: moderate
• 29 to 63: severe ^[1]

CGI (Clinical Global Impression) — severity and improvement scales, 1 to 7. ^[1]

Management — Resuscitation

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Depression itself is rarely a physiological emergency, but several presentations are time-critical: ^[1]

1. Suicidal ideation with plan, intent, and means (acute suicide risk): Do not leave the patient alone. Remove means (medications, ligature points, firearms). Arrange urgent psychiatric assessment and consider involuntary admission under the relevant Mental Health Act if risk is high. Every patient should leave with a structured safety plan (Stanley-Brown Safety Planning Intervention): plan completeness and quality are associated with a reduced likelihood of subsequent suicide attempts and psychiatric rehospitalisation. Prescribe antidepressants in limited quantities where overdose risk exists (tricyclics carry the highest overdose mortality). ^[12]
2. Catatonia with refusal to eat or drink: Medical emergency from dehydration and malnutrition. Admit. Benzodiazepines (usually lorazepam) are highly effective — pooled case-series data show lorazepam dosing from 2 to 60 mg/day (median 8 mg/day) with an overall remission rate of about 55 percent — and ECT is the established next step for benzodiazepine-refractory catatonia. ^[8]
3. Psychotic depression with severe self-neglect or command hallucinations to self-harm: Admit; ECT is the best-evidenced acute biological treatment for severe depressive episodes (bitemporal ECT had the highest response of any stimulation strategy versus sham). ^[4]
4. Severe malnutrition or dehydration from profound retardation: Admit for nutrition/hydration and physical monitoring. ^[1]

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Management — Definitive & Stepwise

Treatment is stepped, matched to severity, and combines pharmacotherapy, psychological therapy, and social interventions. The bio-psycho-social model applies throughout. ^[1]

Step 1 — Recognition, assessment, psychoeducation, and risk

Establish the diagnosis, exclude organic/bipolar causes, assess suicide risk, explain the condition (it is common, treatable, biological, and tends to recur), agree a treatment plan, and address modifiable stressors and substance use.

Step 2 — Mild depression: low-intensity interventions

• Guided self-help based on CBT principles.
• Behavioural activation — structured re-introduction of rewarding activities.
• Group CBT, group mindfulness, or computerised CBT (cCBT, e.g., Beating the Blues).
• Exercise — moderate-intensity, 3 sessions per week (Cochrane-supported modest benefit).
• Sleep hygiene and problem-solving.
• For mild depression, antidepressants are not routinely first-line; consider them only if symptoms persist, history of moderate/severe episodes, or patient preference after an inadequate response to low-intensity care.

Step 3 — Mild to moderate depression not responding, or moderate depression

High-intensity psychological intervention (CBT, interpersonal therapy IPT, or behavioural activation) OR an antidepressant, chosen with the patient. Combination (antidepressant plus high-intensity psychotherapy) is the most effective first-line option for moderate-to-severe depression (NICE).^[3]

Step 4 — Moderate to severe depression: antidepressant plus psychotherapy

Initiate an SSRI as first-line, combined with high-intensity CBT or IPT, with structured follow-up.

Step 5 — Severe, treatment-resistant, psychotic, or catatonic depression

Combination and augmentation strategies, ECT, and specialist multidisciplinary input (see below).

Pharmacological therapy — antidepressants by class

SSRIs (selective serotonin reuptake inhibitors) — first-line. Inhibit reuptake of serotonin at the synaptic cleft; safer in overdose than older agents. ^[1]

Common SSRI adverse effects: nausea/GI upset (transient), headache, agitation/insomnia, sexual dysfunction (anorgasmia, reduced libido, delayed ejaculation), sweating, hyponatraemia due to SIADH (especially elderly — check sodium), increased bleeding risk (platelet dysfunction — caution with NSAIDs/warfarin/DOACs), and rarely serotonin syndrome. ^[1]

SNRIs (serotonin-noradrenaline reuptake inhibitors). In head-to-head network meta-analysis, venlafaxine was among the more effective antidepressants (ORs 1.19 to 1.96 across that group), with smaller differences in acceptability between agents. Physiologically, venlafaxine and duloxetine raise total cholesterol, and duloxetine (with desvenlafaxine and levomilnacipran) raises liver enzymes (AST, ALT, ALP), so lipids and liver function tests are worth monitoring on treatment. ^{[3] [5]}

Atypical / 5-HT modulators. In head-to-head comparisons, mirtazapine and vortioxetine were more effective than other antidepressants, while trazodone was among the least efficacious. Agomelatine was both more effective and better tolerated — with fluoxetine, the only agents associated with fewer dropouts than placebo. Antidepressants also differ physiologically, with up to about a 4 kg difference in weight change between agents, so monitor weight on treatment. ^{[3] [5]}

Tricyclic antidepressants (TCAs) — toxic in overdose; minimise use. Systematic review of fatal-toxicity data shows all TCAs except lofepramine carry substantial overdose mortality; lofepramine had the lowest risk of death in overdose, and desipramine was somewhat more likely than other TCAs to lead to death in overdose. Amitriptyline is the most efficacious antidepressant versus placebo (OR 2.13) but is less tolerable (more dropouts than placebo), and amitriptyline, nortriptyline, and lofepramine were associated with greater in-use cardiotoxicity risk. Prescribe limited quantities where any overdose risk exists. ^{[6] [3]}

Monoamine oxidase inhibitors (MAOIs) — specialist use.

• Phenelzine, tranylcypromine (irreversible, non-selective), moclobemide (reversible inhibitor of MAO-A, RIMA).
• Risk of hypertensive "cheese" crisis with tyramine-rich foods (aged cheese, cured meats, fermented soy, red wine) — dietary restriction needed for irreversible MAOIs.
• Fatal interaction with serotonergic drugs (SSRIs, tramadol, pethidine, dextromethorphan, St John's wort) — serotonin syndrome; a washout of at least 2 weeks (5 weeks after fluoxetine) is required before switching.
• Useful for atypical depression. ^[1]

Prescribing principles

• Start low, go slow; review at 1 to 2 weeks (for tolerability and emerging suicidality) and at 4 weeks for efficacy.
• Full effect takes 4 to 6 weeks. If partial response, continue to 8 weeks before declaring failure.
• Treat for at least 6 to 9 months after remission for a first episode; longer (at least 2 years, often indefinite) for recurrent depression (3 or more episodes, severe episodes, residual symptoms, strong family history).
• Do not stop abruptly — taper over at least 4 weeks to avoid discontinuation syndrome (most pronounced with paroxetine and venlafaxine; least with fluoxetine).
• Choose drug by previous response, side-effect profile, comorbidity, interactions, and pregnancy status. If one SSRI is effective in a family member, that agent is favoured.
• Augmentation strategy after inadequate response to two antidepressant trials:
  • Increase dose to maximum tolerated.
  • Switch class (SSRI to SNRI, or to mirtazapine, bupropion, TCA).
  • Augment with lithium (monitor plasma level 0.4 to 0.8 mmol/L, check renal/thyroid function, ECG in older patients) — robust evidence.
  • Augment with triiodothyronine (T3) 25 to 50 micrograms.
  • Augment with an atypical antipsychotic — aripiprazole (5 to 15 mg), quetiapine (50 to 300 mg), olanzapine — all licensed as adjuncts in MDD.
  • Combination antidepressants (e.g., SSRI plus mirtazapine or bupropion).
  • Brain stimulation — see below. ^[1]

Onset is within days of stopping; duration 1 to 2 weeks (longer with long-acting fluoxetine accumulation). Worst with paroxetine and venlafaxine (short half-lives); least with fluoxetine (long half-life of norfluoxetine). ^[1]

Non-pharmacological biological therapies

• Electroconvulsive therapy (ECT) — most effective acute brain-stimulation treatment for severe or treatment-resistant depression (bitemporal ECT had the highest response versus sham, OR 8.91, and all strategies were at least as acceptable as sham). Rapid effect; side effects include transient confusion and anterograde/retrograde memory loss. Consent and (in urgent cases) Mental Health Act authority required.^[4]
• Repetitive transcranial magnetic stimulation (rTMS) — high-frequency stimulation of the left dorsolateral prefrontal cortex; non-invasive, no anaesthetic; for treatment-resistant depression.
• Transcranial direct current stimulation (tDCS) — emerging.
• Vagus nerve stimulation (VNS) — implanted; chronic/recurrent.
• Deep brain stimulation (DBS) — research/specialist centres.
• Ketamine (intravenous) and esketamine (intranasal, Spravato) — NMDA-receptor antagonists producing rapid (within hours) but transient antidepressant and anti-suicidal effects; specialist use for treatment-resistant depression; monitor for dissociation, BP rise, and potential for misuse.

Psychological therapies

• Cognitive behavioural therapy (CBT) — modifies negative automatic thoughts and cognitive distortions (Beck's triad of self/world/future); first-line for mild-moderate and in combination for severe.
• Interpersonal therapy (IPT) — focuses on role transitions, grief, interpersonal disputes, and deficits.
• Behavioural activation — scheduling of rewarding activities; simple, effective.
• Mindfulness-based cognitive therapy (MBCT) — reduces relapse in recurrent depression when used in remission.
• Psychodynamic psychotherapy — for selected patients with chronic interpersonal difficulties.
• Couples/family therapy, problem-solving therapy, and guided self-help.

Social interventions

Address housing, finances, debt, employment, social isolation, domestic violence, and carer support. Signpost to peer support and voluntary organisations.

Specific Subtypes & Scenarios

• Single episode vs recurrent: a recurrent course predicts further recurrence and justifies longer maintenance treatment after recovery.
• Psychotic depression: high severity with elevated suicide risk; ECT is an acute treatment with strong evidence, and antipsychotic augmentation is an evidence-supported pharmacological option — aripiprazole and quetiapine have the most robust augmentation data. ^{[4] [9]}
• Catatonic depression: benzodiazepines (usually lorazepam) are highly effective first-line treatment, with ECT for refractory cases; address hydration and nutrition. ^[8]
• Seasonal affective disorder (SAD): autumn-winter onset with atypical features (hypersomnia, hyperphagia, fatigue). Light therapy is an established, evidence-based treatment — optimum dose 10,000 lux of white light for 30 to 60 minutes in the early morning, alone or combined with antidepressants. ^[10]
• Peripartum / postnatal depression: onset during pregnancy or after delivery; ask directly about thoughts of harming the infant; treat actively — untreated depression impairs mother-infant bonding and child development.
• Premenstrual dysphoric disorder: luteal-phase affective lability, irritability, and depressed mood resolving with menstruation; diagnose with prospective symptom monitoring.
• Persistent depressive disorder (dysthymia): chronic depressed mood; "double depression" when a major depressive episode is superimposed.
• Disruptive mood dysregulation disorder: children and adolescents with severe recurrent temper outbursts and persistent irritability between outbursts.
• Treatment-resistant depression (TRD): inadequate response to adequate antidepressant trials. Evidence-supported next steps: second-generation antipsychotic augmentation has trial-sequential-analysis-supported efficacy (aripiprazole, quetiapine, brexpiprazole, cariprazine), whereas lithium and T3 augmentation evidence is limited — the lithium benefit was not supported by trial sequential analysis, and T3 showed no significant advantage over control. ^[9]
• Vascular depression (late-onset): later-life onset with executive dysfunction, apathy, and white-matter change on imaging; poorer antidepressant response.
• Secondary depression: treat the underlying cause (e.g., hypothyroidism) and the depression; drug-induced cases resolve on withdrawal. ^[1]

Complications & Pitfalls

• Suicide — the most important complication; untreated depression has well-established adverse consequences, so risk must be assessed and documented at every contact. ^[1]
• Self-harm, functional impairment, substance misuse, cognitive impairment, and relapse or chronicity all complicate the illness and its undertreatment. ^[1]
• Antidepressant adverse effects:
  • GI upset, headache, sexual dysfunction, sweating (SSRIs).
  • Cholesterol rises with venlafaxine, duloxetine, desvenlafaxine, and paroxetine; liver enzymes (AST, ALT, ALP) rise with duloxetine, desvenlafaxine, and levomilnacipran — magnitudes usually not clinically significant. ^[5]
  • The same physiological network meta-analysis found no strong evidence of clinically significant effects on QTc or sodium concentrations with the antidepressants studied. ^[5]
  • Citalopram QTc — the FDA advises against doses over 40 mg/day because of dose-dependent QTc prolongation; in a retrospective cohort, the prevalence of QTc prolongation increased with dose. ^[7]
  • TCA overdose toxicity — TCAs other than lofepramine carry substantial overdose mortality; lofepramine had the lowest risk of death in overdose; minimise TCA use where overdose risk exists. ^[6]
  • MAOI hypertensive crisis with tyramine-rich foods and serotonergic drug interactions — specialist prescribing only.
  • Switching to mania in bipolar depression — always screen for past hypomania before prescribing.
• Diagnostic pitfalls: missing bipolar depression (and triggering mania), missing organic causes, confusing grief with depression, and under-treating psychotic or catatonic depression. ^[1]

Prognosis & Disposition

• First episode: approximately 50 percent recover fully; of those who recover, around 50 percent relapse within 2 years.
• Recurrence risk rises with each episode: 50 percent after one, 70 percent after two, 90 percent after three or more — justifying maintenance treatment after 2 to 3 episodes.
• Predictors of good outcome: early and vigorous treatment, good social support, no comorbidity, late age of onset of first episode of certain subtypes, good response to first treatment.
• Predictors of poor outcome: chronicity, psychotic features, comorbid anxiety/substance use/personality disorder, cognitive impairment, medical comorbidity, family history of bipolar disorder, non-adherence, severe psychosocial stressors.
• Mortality: raised from suicide, cardiovascular disease, and poor self-care. Depression reduces life expectancy.
• Disposition: most patients are managed in primary care with psychological therapy and an SSRI. Indications for psychiatric referral or admission: active suicide risk, psychotic features, catatonia, severe self-neglect, diagnostic uncertainty (suspected bipolar, organic cause), treatment resistance, need for ECT, child-protection concerns, and severe peripartum depression. Discharge planning includes a written safety plan, crisis contacts, follow-up within 1 to 2 weeks of starting treatment, and clear escalation pathways. ^[1]

Special Populations

Pregnancy and breastfeeding

• Treat actively — untreated antenatal depression harms mother and fetus (poor nutrition, substance use, non-attendance, postnatal depression, impaired bonding).
• Sertraline is preferred (lowest transfer into breast milk and least teratogenic signal); fluoxetine and citalopram are alternatives.
• Paroxetine is best avoided in the first trimester (associations with cardiac septal defects) and third trimester (neonatal irritability/poor neonatal adaptation syndrome).
• Do not stop antidepressants abruptly in pregnancy — relapse risk is high.
• ECT is safe and effective in pregnancy for severe/psychotic depression.
• Avoid MAOIs (hypertensive crisis, teratogenicity); avoid TCAs in overdose risk; bupropion has congenital cardiac concerns.
• Coordinate with obstetrics and perinatal mental health services; beware of postpartum psychosis (a separate emergency, usually bipolar-spectrum).

Elderly

• Higher completed-suicide risk (especially elderly men). Lower starting dose ("start low, go slow") — sertraline 25 to 50 mg, citalopram 10 to 20 mg (max 20 mg).
• Beware hyponatraemia (SIADH) and falls — check sodium.
• Beware QT prolongation — ECG before citalopram/escitalopram.
• Watch for pseudodementia, somatic and psychotic presentations, and drug interactions (polypharmacy).
• ECT is safe, effective, and often preferred in severe/psychotic/catatonic elderly depression. ^[1]

Children and adolescents

• Fluoxetine is first-line (most evidence; TADS showed fluoxetine plus CBT best). Sertraline and escitalopram are alternatives.
• CBT and IPT are first-line psychosocial treatments.
• Black-box warning: antidepressants may increase suicidality in those under 25 — close monitoring in the first 1 to 4 weeks.
• Avoid TCAs (cardiotoxic, poorly tolerated, limited evidence) and paroxetine (increased suicidality).
• Family involvement, school liaison, and safeguarding assessment are essential.

Patients with comorbid medical conditions

• Post-myocardial infarction / cardiac disease: sertraline is the SSRI of choice (safe on cardiac conduction; SERTRAP trial). Avoid TCAs (arrhythmogenic).
• Epilepsy: SSRIs (sertraline, citalopram) preferred; avoid bupropion (lowers seizure threshold).
• Hepatic impairment: reduce doses; avoid agomelatine (hepatotoxic); monitor LFTs.
• Renal impairment: reduce doses of renally cleared drugs (e.g., duloxetine, lithium).
• Diabetes: SSRIs may initially worsen glycaemic control, then stabilise; mirtazapine/paroxetine/TCAs worsen weight.
• Bleeding risk / anticoagulated: SSRIs increase bleeding — consider mirtazapine or bupropion; co-prescribe a proton-pump inhibitor if NSAIDs also used.

Evidence, Guidelines & Regional Differences

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Landmark evidence

• Cipriani et al. 2018 (Lancet, network meta-analysis of 21 antidepressants in 522 trials): all 21 antidepressants were more efficacious than placebo; agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were the most effective; fluoxetine was the most tolerable. Head-to-head, amitriptyline, escitalopram, and mirtazapine had the best efficacy-tolerability balance.^[3]
• STAR*D (Sequenced Treatment Alternatives to Relieve Depression): remission with citalopram at level 1 was about 28 to 33 percent; cumulative remission across four sequential levels approached 70 percent, but relapse rates were high — emphasising the chronicity of TRD.
• Mutz et al. 2019 (BMJ, network meta-analysis of brain stimulation): bitemporal ECT had the highest response versus sham (OR 8.91); high-dose right unilateral ECT and bilateral rTMS were also effective; all strategies were at least as acceptable as sham.^[4]
• TADS (Treatment for Adolescents with Depression Study): fluoxetine plus CBT was the most effective and safest treatment for adolescent depression; fluoxetine alone increased suicidality signals — supports combination treatment and monitoring.
• GBD studies: depression is the single largest contributor to non-fatal health loss (years lived with disability) globally.
• MHRA/EMA warnings: citalopram and escitalopram QT prolongation (dose limits); antidepressant-related suicidality in under-25s.

Controversies

• Whether antidepressants are over-prescribed for mild depression (NICE now limits first-line use).
• The role of inflammation and the gut microbiome (emerging).
• Long-term risks of antidepressant use (sexual dysfunction, weight gain, withdrawal).
• Efficacy of ketamine/esketamine for routine TRD and suicide prevention.
• Whether screening programmes in primary care improve outcomes.

Exam Pearls

• Diagnosis is clinical: depressed mood, diminished interests, impaired cognitive function, and vegetative symptoms (disturbed sleep or appetite) with functional impairment. ^[2]
• All antidepressants are more effective than placebo (network meta-analysis of 522 trials, 116,477 participants); individualise the choice by efficacy, acceptability, physiology, and patient preference. ^[3]
• PHQ-9 — a score of 10 or more has 88 percent sensitivity and 88 percent specificity for major depression; scores of 5, 10, 15, and 20 represent mild, moderate, moderately severe, and severe depression. ^[11]
• Citalopram — FDA warning against doses over 40 mg/day for dose-dependent QTc prolongation. ^[7]
• ECT — bitemporal ECT had the highest response of any brain stimulation strategy versus sham (OR 8.91). ^[4]
• Always screen for bipolar disorder before starting an antidepressant (antidepressant monotherapy can precipitate mania).
• TCAs are toxic in overdose — all except lofepramine; lofepramine has the lowest risk of death in overdose; minimise use. ^[6]
• Treatment-resistant depression — augment with an evidence-supported second-generation antipsychotic (aripiprazole, quetiapine, brexpiprazole, cariprazine); evidence for lithium and T3 augmentation is limited. ^[9]
• Seasonal depression — light therapy at 10,000 lux white light, 30 to 60 minutes, early morning. ^[10]
• Beck's cognitive triad — negative views of self, world, and future.
• Grief vs depression: grief comes in waves, self-esteem preserved, thoughts of deceased; depression is pervasive, with worthlessness and hopelessness.
• Pseudodementia — abrupt onset, "I don't know" answers, poor effort, variable, improves with treatment of depression (contrast dementia). ^[1]

Exam application bank (NEET-PG / INICET)

One-line answer

Major depressive disorder is a common, relapsing-remitting mood disorder defined by 5 or more SIGECAPS symptoms present most of the day, nearly every day, for at least 2 weeks, including depressed mood or anhedonia. First-line treatment is an SSRI (sertraline) combined with CBT; ECT is reserved for severe, psychotic, or catatonic depression. Suicide risk must be assessed at every contact.

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose/route if drug therapy is standard. ^[1]

Stem 2 — Unstable / complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote, or reperfusion — and what you do in the first 15 minutes. ^[1]

Stem 3 — Atypical group. Elderly, pregnancy, child, or immunocompromised: how presentation and thresholds change. ^[1]

Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. ^[1]

Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU/ICU/theatre, and what follow-up is mandatory. ^[1]

Rapid viva checklist

1. Definition + classification
2. Pathophysiology chain
3. Bedside signs / criteria
4. Score with exact components (if any)
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline/trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Depression.

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References12ShowHide

1. [1]McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Ann Intern Med, 2021.PMID 33971098
2. [2]Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF. Major depressive disorder. Nat Rev Dis Primers, 2016.PMID 27629598
3. [3]Cipriani A, Furukawa TA, 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.PMID 29477251
4. [4]Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ, 2019.PMID 30917990
5. [5]Pillinger T, Arumuham A, McCutcheon RA, et al. The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis. Lancet, 2025.PMID 41135546
6. [6]Taylor DM, Poulou S, Clark I. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use. Ther Adv Psychopharmacol, 2024.PMID 38827015
7. [7]McClelland J, Mathys M. Evaluation of QTc prolongation and dosage effect with citalopram. Ment Health Clin, 2016.PMID 29955465
8. [8]Bot L, Schotsman B, Oostra E, et al. The Effect of Benzodiazepines on Catatonia: A Systematic Review and Meta-Analysis. Acta Psychiatr Scand, 2026.PMID 42009596
9. [9]Hsu TW, Hsu CW, Thompson T, et al. Reappraising lithium, triiodothyronine and second-generation antipsychotic augmentation treatment for major depression: a systematic review and meta-analysis with bias-adjustment analyses. BMJ Ment Health, 2026.PMID 42532626
10. [10]Wirz-Justice A, Terman AM. CME: Light Therapy: Why, What, for Whom, How, and When (And a Postscript about Darkness). Praxis (Bern 1994), 2022.PMID 35105211
11. [11]Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med, 2001.PMID 11556941
12. [12]Kearns JC, Crasta D, Spitzer EG, et al. Evaluating the Effectiveness of Safety Plans for Mitigating Suicide Risk in Two Samples of Psychiatrically Hospitalized Military Veterans. Behav Ther, 2025.PMID 40010911