Key Facts

Depression affects ~1 in 6 UK adults. Antidepressants are effective for moderate-severe depression and many anxiety disorders. The choice of antidepressant should consider efficacy, side effect profile, safety in overdose, and patient preference.

Classification

• SSRIs: sertraline, fluoxetine, citalopram, escitalopram, paroxetine
• SNRIs: venlafaxine, duloxetine, desvenlafaxine
• TCAs: amitriptyline, nortriptyline, clomipramine, imipramine, dosulepin
• MAOIs: phenelzine, tranylcypromine, moclobemide (reversible — RIMA)
• Others: mirtazapine (NaSSA), trazodone, vortioxetine, agomelatine, bupropion

Pharmacology

• SSRIs: selectively inhibit SERT → ↑ synaptic serotonin
• SNRIs: inhibit both SERT and NET → ↑ serotonin and noradrenaline
• TCAs: inhibit SERT and NET (non-selectively) + block muscarinic, histamine H1, and alpha-1 receptors → side effects
• MAOIs: inhibit monoamine oxidase → ↑ serotonin, noradrenaline, dopamine
• Mirtazapine: antagonist at alpha-2, 5-HT2, 5-HT3, H1 receptors → ↑ noradrenaline and serotonin

Pathophysiology

• Monoamine hypothesis: depression associated with reduced serotonin, noradrenaline, and/or dopamine neurotransmission
• Antidepressants increase monoamine availability → downstream neuroplastic changes → therapeutic effect (delayed 4–6 weeks)
• Neuroplasticity/BDNF hypothesis: antidepressants promote neurogenesis and synaptic plasticity in hippocampus

Indications

• Depression: moderate-severe (with or without anxiety)
• Generalised anxiety disorder: SSRIs, SNRIs
• OCD: SSRIs (fluoxetine, sertraline) — often higher doses; clomipramine
• PTSD: SSRIs, trauma-focused CBT
• Panic disorder: SSRIs
• Neuropathic pain: amitriptyline 10–75 mg, duloxetine 60 mg (NICE CG173)
• Migraine prophylaxis: amitriptyline 10–50 mg ON
• Fibromyalgia: amitriptyline, duloxetine

Common Side Effects

• SSRIs: GI (nausea, diarrhoea), sexual dysfunction (~30–40%), insomnia/drowsiness, headache, increased anxiety initially, hyponatraemia (SIADH — especially elderly)
• SNRIs: as SSRIs + sweating, hypertension (venlafaxine at higher doses), discontinuation syndrome (venlafaxine worst)
• TCAs: anticholinergic (dry mouth, constipation, urinary retention, blurred vision), sedation, weight gain, postural hypotension, cardiac toxicity in overdose (QRS prolongation, arrhythmia)
• Mirtazapine: sedation, increased appetite/weight gain, rarely agranulocytosis
• MAOIs: tyramine reaction ('cheese reaction') — hypertensive crisis with tyramine-containing foods; serotonin syndrome

Red Flags

• Suicidality: monitor closely in first 2–4 weeks of treatment (especially young adults)
• Serotonin syndrome: combining serotonergic drugs → agitation, clonus, hyperthermia, diaphoresis, tachycardia
• TCA overdose: lethal in overdose — QRS prolongation, seizures, coma; treat with IV sodium bicarbonate
• Hyponatraemia: SSRIs in elderly → confusion, seizures; check Na if symptomatic

Before Starting

• Baseline assessment: PHQ-9, GAD-7 for depression/anxiety severity
• Suicide risk assessment: essential at every review
• ECG: if prescribing TCA (QTc) or citalopram/escitalopram (QT prolongation)
• U&Es: baseline Na (SIADH risk, especially elderly on SSRIs)
• LFTs: agomelatine (hepatotoxicity monitoring required)

Monitoring

• Review at 2 weeks: after initiation — assess side effects, suicidality
• PHQ-9: repeat at each review — track treatment response
• Review at 4–6 weeks: assess efficacy — inadequate response → increase dose, switch, or augment
• Na+: if elderly patient develops confusion on SSRI → check Na
• BP: if on venlafaxine (dose-dependent hypertension)

Special Tests

• ECG: if QT-prolonging antidepressant (citalopram max 20 mg in >65s — MHRA; escitalopram max 10 mg in >65s)
• TDM: not routine for most antidepressants; available for TCAs, lithium

Stepped Care (NICE NG222)

1. Subthreshold/mild: watchful waiting, guided self-help, exercise, psychological interventions
2. Moderate: SSRI + psychological therapy (CBT preferred)
3. Severe: SSRI + CBT; consider higher-intensity psychological therapy
4. Treatment-resistant: switch SSRI → different SSRI or SNRI or mirtazapine; augmentation (lithium, quetiapine, aripiprazole)

First-Line Prescribing

• Sertraline 50 mg OD → 100–200 mg: preferred SSRI; fewest drug interactions
• Fluoxetine 20 mg OD → 60 mg: long half-life (less discontinuation); preferred in adolescents
• Citalopram 20 mg OD → 40 mg: QT prolongation risk — max 20 mg in >65s (MHRA)

Duration

• Continue for at least 6 months after remission (first episode)
• 2+ years for recurrent depression (≥2 episodes)
• Lifelong consideration for 3+ severe episodes

Discontinuation

• Taper gradually over 4+ weeks (longer for paroxetine, venlafaxine)
• Discontinuation syndrome: dizziness, paraesthesia ('brain zaps'), GI upset, insomnia, irritability
• NOT the same as addiction — reassure patients

Referral Criteria

• Psychiatry: treatment-resistant depression (failed 2 adequate trials), severe with psychotic features, high suicide risk
• Crisis team: acute suicidal ideation with plan
• IAPT/psychological therapies: CBT, counselling

• ~50% of patients respond to first-line SSRI
• ~70% respond to second antidepressant if first fails
• STAR*D trial: cumulative remission ~67% after 4 treatment steps
• Relapse: ~50% within 2 years of stopping treatment (first episode); higher with recurrent depression
• Combination of antidepressant + CBT: most effective for moderate-severe depression
• TCA overdose: potentially fatal — cardiac arrhythmia, seizures → prescribe in limited quantities if suicide risk

SSRI Comparison

Antidepressant Side Effect Profile