Depression — Causes, Symptoms, Diagnosis & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Major depressive disorder (MDD) is a serious, episodic mental health disorder characterised by a persistent depressed mood or loss of interest and pleasure (anhedonia), accompanied by a cluster of cognitive, physical, and behavioural symptoms lasting at least 2 weeks, causing significant functional impairment. Depression is not simply 'feeling sad' — it represents a distinct neurobiological illness involving dysregulation of monoamine neurotransmitters (serotonin, noradrenaline, dopamine), hypothalamic-pituitary-adrenal (HPA) axis hyperactivation with elevated cortisol, inflammatory cytokine elevation (IL-6, TNF-alpha — the 'inflammatory hypothesis' of depression), structural brain changes (hippocampal atrophy from glucocorticoid neurotoxicity), and disrupted reward circuitry (reduced nucleus accumbens activity). The WHO reports 280 million people worldwide are affected by depression, making it the leading cause of disability globally, and a major contributor to the overall global burden of disease. Depression significantly increases the risk of medical morbidity (cardiovascular disease, stroke, diabetes) and mortality. Approximately 50% of people with depression experience recurrent episodes; chronic or treatment-resistant depression affects 20-30%. The standard classification includes major depressive disorder (MDD), persistent depressive disorder (PDD/dysthymia — milder but chronic, lasting years), premenstrual dysphoric disorder (PMDD), and depressive episodes in bipolar disorder.

Depression is a multifactorial disorder arising from the interaction of biological vulnerability (genetic predisposition), psychological factors, and environmental stressors. Neurobiological: monoamine deficiency (serotonin, noradrenaline, dopamine — the basis of antidepressant pharmacology); HPA axis dysregulation (elevated cortisol from chronic stress causes hippocampal damage and impairs neuroplasticity); reduced BDNF (brain-derived neurotrophic factor — antidepressants raise BDNF, supporting the neurogenesis hypothesis of depression); neuroinflammation (cytokine-driven — inflammation causes 'sickness behaviour' resembling depression); genetic predisposition (heritability 37% for MDD — linked to serotonin transporter gene 5-HTTLPR, BDNF Val66Met polymorphism). Psychological factors: cognitive vulnerabilities (negative cognitive triad — Beck's model: negative views of self, world, and future); childhood adversity (abuse, neglect, parental mental illness — epigenetic changes; major risk factor for depression throughout life); adverse life events (bereavement, relationship breakdown, financial crisis, job loss — interact with genetic and psychological vulnerability — 'stress-diathesis' model); neuroticism (personality trait — key predictor); and learned helplessness. Medical conditions causing or worsening depression: hypothyroidism, Cushing's syndrome, Parkinson's disease, stroke, multiple sclerosis, cancer, chronic pain, coronary heart disease, COPD, and sleep disorders (bidirectional relationship). Medications: beta-blockers, corticosteroids, oral contraceptives (in susceptible individuals), anticonvulsants, interferon-alpha, isotretinoin. Social risk factors: social isolation; poverty and deprivation; unemployment; domestic violence; discrimination (LGBTQ+ individuals have 3x higher depression prevalence); and perinatal depression (10-15% of new mothers; also affects fathers — 10%).

ICD-11/DSM-5 require the presence of at least one core symptom plus additional symptoms representing a change from previous functioning, present most of the day, nearly every day, for at least 2 weeks, causing significant distress or functional impairment. Core symptoms (at least one required): (1) Depressed mood most of the day — persistent sadness, emptiness, hopelessness, tearfulness; (2) Anhedonia — markedly diminished interest or pleasure in all or most activities that were previously enjoyable. Additional symptoms (further from this list): fatigue or loss of energy; changes in sleep (insomnia — especially early morning wakening — or hypersomnia); psychomotor agitation or retardation (observable by others); appetite or weight change (decreased or increased by 5%+ body weight in a month); difficulty concentrating, thinking, or making decisions; feelings of worthlessness or excessive/inappropriate guilt; and recurrent thoughts of death or suicide, suicidal ideation, suicide plan, or suicide attempt. Validated severity scales: PHQ-9 (Patient Health Questionnaire-9) — 9 questions rating each DSM symptom 0-3 over 2 weeks; scores: 5-9 (mild), 10-14 (moderate), 15-19 (moderately severe), 20+ (severe); a PHQ-9 score of 10+ indicates likely major depression. Hamilton Depression Rating Scale (HDRS) and Montgomery-Asberg Depression Rating Scale (MADRS) are used in clinical trials. Psychotic depression: severe depression with hallucinations (typically auditory — voices saying negative things) or delusions (worthlessness, guilt, somatic delusions, nihilistic delusions). Melancholic features: anhedonia, early morning wakening, morning worsening, psychomotor changes, guilt, weight loss — predict better response to antidepressants and ECT. Bipolar depression: depressive episodes in bipolar disorder require different management — antidepressants alone can trigger mania or rapid cycling.

Depression is a clinical diagnosis based on clinical interview and validated symptom scales — there is no definitive biological test. However, investigations are essential to exclude medical causes and assess for comorbidities. Clinical assessment: structured clinical interview using DSM-5 or ICD-11 criteria; validated rating scales (PHQ-9 for primary care, HDRS, MADRS); risk assessment for suicide and self-harm (Columbia Suicide Severity Rating Scale — C-SSRS); assess for bipolar disorder (past manic/hypomanic episodes — NICE recommends the HCL-32 or Mood Disorder Questionnaire screening); identify current medications (drug-induced depression); and collateral history from close contacts. Medical investigations to exclude organic causes: thyroid function tests (hypothyroidism causes depression — TSH first-line); FBC (anaemia); blood glucose and HbA1c; calcium (hypercalcaemia — 'bones, groans, moans, stones'); vitamin B12 and folate (B12 deficiency causes neuropsychiatric symptoms); LFTs (liver disease); renal function; and cortisol if Cushing's syndrome suspected. MRI brain: indicated if new neurological signs, sudden onset of depression in the elderly, or features suggesting intracranial pathology. Sleep assessment: insomnia (assess for OSA — STOP-BANG questionnaire). Differentiate from: generalised anxiety disorder (can coexist — treat both); bipolar disorder (critical distinction — antidepressants alone worsen bipolar); schizophrenia (psychotic features can overlap); ADHD; personality disorders; and grief (normal grief is not a mental disorder — but can transition into MDD).

Treatment is stepped-care, based on severity. Mild depression: watchful waiting (if symptoms are brief); guided self-help based on CBT principles; structured exercise programmes (NICE recommends 3x 45-60 minutes aerobic exercise per week — reduces depression by 30-50% comparable to antidepressants in mild-moderate depression); and psychosocial support (social prescribing, problem-solving therapy). Moderate-to-severe depression: antidepressants (first-line) and/or evidence-based psychotherapy. Antidepressants: SSRIs (selective serotonin reuptake inhibitors) — first-line: sertraline (most evidence for cardiovascular safety and tolerability), fluoxetine (also used for eating disorders and PMDD — long half-life), escitalopram and citalopram (well tolerated), paroxetine (more discontinuation symptoms — avoid in pregnancy). SNRIs (serotonin-noradrenaline reuptake inhibitors): venlafaxine, duloxetine (also for generalised anxiety, chronic pain). Mirtazapine: noradrenergic and specific serotonergic antidepressant (NaSSA) — particularly useful for insomnia and weight loss in depression; sedating; fewer sexual side effects. Tricyclic antidepressants (amitriptyline, nortriptyline): effective but more side effects and dangerous in overdose; reserved for pain management and refractory depression. MAOIs (phenelzine, tranylcypromine): powerful but complex — dietary tyramine restrictions (cheese, cured meats) to avoid hypertensive crisis; reserved for specialist use. Antidepressant response: improvement typically seen by 4-6 weeks; full response by 8-12 weeks; continue for 6-12 months after remission (or 2+ years after recurrent episodes) to prevent relapse. Psychotherapy: CBT (cognitive behavioural therapy — gold standard for depression; 16-20 sessions; as effective as antidepressants for moderate depression; combination superior to either alone); IPT (interpersonal therapy); behavioural activation; mindfulness-based cognitive therapy (MBCT — recommended by NICE for relapse prevention); and problem-solving therapy. Treatment-resistant depression (TRD — failure of 2+ adequate antidepressant trials): augmentation strategies (lithium addition, atypical antipsychotics — aripiprazole, quetiapine, olanzapine); ketamine/esketamine (intranasal esketamine — Spravato — FDA approved 2019; rapid-onset antidepressant effect within hours; for TRD and acute suicidality); ECT (electroconvulsive therapy — highly effective in severe or treatment-resistant depression, psychotic depression, and catatonia — response rate 60-80%; misconceptions from popular media — modern ECT is performed under general anaesthesia and is safe); TMS (transcranial magnetic stimulation — non-invasive brain stimulation); and psychedelic-assisted therapy (psilocybin — phase 3 trials showing promising results).

Untreated or inadequately treated major depression carries significant complications. Recurrence is the most common complication — up to 80–90% of patients with two or more prior episodes will experience further episodes without ongoing treatment; each episode increases neurobiological vulnerability. Suicide is the most serious complication — approximately 3.4% of people with major depressive disorder die by suicide over their lifetime; risk is highest in the first weeks after hospital discharge and during antidepressant initiation. Cognitive impairment (memory, concentration, executive function, processing speed) can persist between episodes, particularly in treatment-resistant or recurrent depression — hippocampal atrophy from chronic hypercortisolaemia is a neurobiological mechanism. Cardiovascular disease risk is elevated 1.5–2-fold — depression is an independent cardiovascular risk factor, partly mediated by autonomic dysfunction, inflammation, and reduced health behaviours. Physical health comorbidities — chronic pain, metabolic syndrome, immune dysregulation — both cause and worsen depression in a bidirectional relationship. Social complications include relationship breakdown, unemployment, and social isolation.

Primary prevention of first-episode depression: mindfulness-based stress reduction (MBSR) programmes in high-risk individuals reduce depression incidence; early intervention in childhood adversity; addressing social determinants (poverty, social isolation, domestic violence); physical activity (the most evidence-based protective factor — 2-3 hours/week of moderate exercise reduces depression risk by 25-35%); adequate sleep; social connection; and management of chronic medical conditions. Secondary prevention (preventing relapse after recovery): maintenance antidepressant therapy (continued for 6-12 months after remission, 2+ years after recurrent episodes — reduces relapse risk by 50%); mindfulness-based cognitive therapy (MBCT — recommended by NICE for patients with 3+ prior episodes — reduces relapse risk by 44%); ongoing psychotherapy; and monitoring early warning signs. Protective factors: social support networks; sense of purpose; engaging meaningful activities; treatment of physical illness; employment; and cognitive engagement. Mental health first aid training enables early identification and support. Anti-stigma campaigns encourage help-seeking, reducing the 11-year average delay between symptom onset and treatment for mental health conditions.

Seek emergency care immediately — call 999, go to A&E, or call the Samaritans (116 123 in the UK): if you are having active thoughts of suicide with intent or a plan; if you have taken an overdose or self-harmed; or if you feel you cannot keep yourself safe. Call a crisis team or mental health crisis line if: you are experiencing suicidal thoughts but are not in immediate danger; you are experiencing psychotic symptoms (voices, delusions); or your usual mental health team is unavailable. See your GP promptly (within 1 week) for: persistent low mood, anhedonia, hopelessness, or anxiety lasting more than 2 weeks; sleep disturbance, appetite change, or significant fatigue that is affecting daily functioning; passive thoughts of death or self-harm (even without intent); and any depression symptoms in a person with a history of previous depression. Do not wait until symptoms are severe before seeking help — early treatment produces better outcomes. Many people delay seeking help for depression out of shame, minimising their symptoms, or believing they should manage alone — but depression is a medical condition and is highly treatable.