Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine) are first-line drugs for depression and anxiety disorders. They are better tolerated and much safer in overdose than tricyclic antidepressants.

Mechanism. They block the serotonin transporter, raising synaptic serotonin. Downstream receptor changes over 2 to 4 weeks produce the antidepressant and anxiolytic effect.

Pharmacokinetics. Half-lives: fluoxetine 1 to 3 days (norfluoxetine 7 to 15 days), sertraline 26 hours, paroxetine 21 hours, citalopram 35 hours, escitalopram 30 hours, fluvoxamine 15 hours. Fluoxetine and paroxetine strongly inhibit CYP2D6. Fluvoxamine strongly inhibits CYP1A2 and CYP2C19.

Differences. Escitalopram and sertraline have the best tolerability profile. Paroxetine causes the most discontinuation symptoms, weight gain and anticholinergic effects. Fluoxetine has the longest half-life and the least discontinuation effect. Citalopram has dose-related QT prolongation. Fluvoxamine causes the most interactions.

• Depression, generalised anxiety, social anxiety, panic, post-traumatic stress and obsessive-compulsive disorder: all agents, with higher doses for obsessive-compulsive disorder.
• Bulimia nervosa: fluoxetine 60 mg daily.
• Premenstrual dysphoric disorder: continuous or luteal phase dosing.
• Premature ejaculation: paroxetine or dapoxetine, as needed or daily.
• Starting: a low dose in anxiety to avoid early activation (jitteriness), with a benzodiazepine for a short time in severe cases. Increase every 1 to 2 weeks.
• Switching: cross taper for most SSRIs; allow 5 weeks after stopping fluoxetine before starting a monoamine oxidase inhibitor.

Special groups. Pregnancy: sertraline preferred; paroxetine avoided; third trimester exposure can cause a neonatal adaptation syndrome (jitteriness, feeding difficulty, resolving in days) and a small increase in persistent pulmonary hypertension. Breastfeeding: sertraline and paroxetine preferred; fluoxetine and citalopram give higher infant levels.

Children: fluoxetine, escitalopram and sertraline (for obsessive-compulsive disorder) under specialist care. Older adults: use sertraline or escitalopram, limit citalopram to 20 mg, and check sodium at 2 and 4 weeks. Kidney impairment: no adjustment for sertraline. Liver impairment: halve the dose. Regional: ritonavir raises levels of several SSRIs, and tuberculosis drugs rarely interact; fluoxetine is widely available.

Adverse effects. Nausea and diarrhoea early, sexual dysfunction, insomnia or somnolence, sweating, tremor, hyponatraemia, bleeding (add a proton pump inhibitor when combined with an NSAID or anticoagulant), serotonin syndrome, discontinuation symptoms (dizziness, paraesthesia, irritability), and reduced bone density.

Contraindications. Monoamine oxidase inhibitors within 14 days (5 weeks for fluoxetine), linezolid, and pimozide or thioridazine with citalopram and escitalopram.

Interactions. Tramadol, triptans and methylene blue (serotonin syndrome); warfarin and NSAIDs (bleeding); tamoxifen with fluoxetine or paroxetine (less active endoxifen, avoid); codeine (reduced analgesia through CYP2D6 inhibition); clozapine with fluvoxamine (levels rise 5-fold or more).

Monitoring. Suicidality at 1 week and then regularly; sodium at 2 and 4 weeks in older adults; ECG with citalopram in cardiac disease; bleeding and weight.

Referral and escalation. Serotonin syndrome, severe hyponatraemia (sodium under 125 mmol/L), mania, or suicidal intent.