Antidepressants

Antidepressants are drugs used to treat major depressive disorder and, with the same or different dose ranges, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder, bulimia nervosa, neuropathic pain and enuresis. They raise synaptic monoamine signalling, and over weeks promote receptor adaptation and neuroplasticity. Their benefit over placebo is moderate in mild depression and clearer in moderate to severe depression.

Classification. Selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, atypical agents (mirtazapine, bupropion, agomelatine, esketamine) and serotonin modulators (vortioxetine, vilazodone, trazodone).

Onset. Some improvement appears in 1 to 2 weeks, with full effect at 4 to 8 weeks. Absence of any improvement by 2 to 4 weeks at an adequate dose predicts poor response.

Efficacy. Differences in efficacy between classes are small. Venlafaxine, escitalopram, sertraline and mirtazapine rank slightly higher, and reboxetine and trazodone lower. Choice is driven mainly by tolerability, comorbidity, interactions, safety in overdose and cost.

• First-line: an SSRI (sertraline or escitalopram) for most patients. Start at a low dose in anxiety and in older adults, and increase after 1 to 2 weeks.
• Adequate course: 6 to 8 weeks at the target dose before judging failure. Review at 1 to 2 weeks for tolerability and risk.
• Continuation: at least 6 to 12 months after remission; 2 years or longer after 2 or more episodes or with severe or chronic illness.
• Stopping: taper over 4 weeks or longer, more slowly after long courses or with short half-life agents (paroxetine, venlafaxine).
• Non-response: confirm adherence and diagnosis, increase to the maximum dose, then switch class, or augment with lithium (serum level 0.6 to 0.8 mmol/L), aripiprazole 2 to 15 mg, or quetiapine extended release 150 to 300 mg. Add psychological therapy at any stage.
• Screen for bipolar disorder before starting, as antidepressant monotherapy can induce mania.

Special groups. Pregnancy: sertraline is the usual choice; avoid paroxetine (cardiac malformations). Breastfeeding: sertraline and paroxetine give low infant exposure. Children and young people: fluoxetine from 8 years and escitalopram from 12 years, with psychological therapy first in mild illness. Older adults: avoid tricyclics; limit citalopram to 20 mg daily; check sodium.

Kidney impairment: most need no change; adjust venlafaxine and duloxetine. Liver impairment: halve doses. Regional: amitriptyline and fluoxetine are the antidepressants most often stocked in the region, and efavirenz, ritonavir and rifampicin alter levels of several agents. Depression with HIV, tuberculosis or chronic disease is common and treated in the same way.

Adverse effects. Nausea, sexual dysfunction (30 to 60% on SSRIs), sleep disturbance, weight change, sweating, hyponatraemia (older adults), bleeding (worse with NSAIDs and anticoagulants), QT prolongation (citalopram), serotonin syndrome, discontinuation symptoms, and mania.

Suicidality. A boxed concern applies to people under 25 in the first weeks. Review at 1 week, then every 1 to 2 weeks until risk is stable.

Serotonin syndrome. Agitation, tremor, clonus, hyperreflexia, hyperthermia, diarrhoea and sweating within 24 hours of starting, raising the dose or combining serotonergic drugs. Stop the drugs and give supportive care.

Interactions. Monoamine oxidase inhibitors with any other antidepressant (contraindicated), linezolid, tramadol, triptans and methylene blue.

Monitoring. Mood and risk, sodium at 2 to 4 weeks in older adults and those on diuretics, blood pressure with SNRIs, ECG with citalopram in cardiac disease, and weight.

Referral and escalation. Suicidal intent, psychosis, mania, two failed courses, or pregnancy planning.