Antidepressants: types, mechanism of action, clinical effects, adverse effects, indications, and monitoring

01Drug classification

Antidepressants are grouped by what they act on. Their history began by chance, with drugs made for other purposes.

1. 1952 to 1957

   Iproniazid and imipramine

   Iproniazid, a tuberculosis drug, lifts the mood of patients and becomes the first monoamine oxidase inhibitor. Roland Kuhn in Switzerland finds that imipramine, tested as an antipsychotic, treats depression: the first tricyclic.

2. 1960s

   The monoamine hypothesis

   These drugs, and reserpine's power to cause depression, suggest that depression is a lack of noradrenaline and serotonin.

3. 1987

   Fluoxetine

   The first widely used selective serotonin reuptake inhibitor is licensed in the US, safer in overdose than the tricyclics.

4. 1990s and 2000s

   Dual and new mechanisms

   Venlafaxine, mirtazapine and duloxetine follow, then agomelatine (EU 2009) and vortioxetine (2013).

5. 2019 to 2025

   Beyond the monoamines

   Esketamine nasal spray is licensed in the US and EU in 2019; zuranolone, a neurosteroid, for postnatal depression in the US in 2023 and the EU in 2025.

02Pharmacokinetics

Antidepressants are taken by mouth, once a day for most, and are well absorbed, fat-soluble and largely protein-bound. The liver clears them, and several block the cytochromes that clear other drugs, which is what most of their interactions come from.

CYP2D6 varies between people: poor metabolisers, about 1 in 15 Europeans, reach high levels of tricyclics, venlafaxine and vortioxetine. By blocking it, fluoxetine and paroxetine raise tricyclic levels, cut the conversion of codeine to morphine, and leave tamoxifen less able to form its active metabolite.

03Pharmacodynamics

Most antidepressants raise serotonin, noradrenaline or both at the synapse, by blocking their reuptake transporters, blocking the monoamine oxidase that breaks them down, or blocking receptors that hold back their release.

1. 1

   Hours

   Transporters are blocked and monoamines rise at the synapse, but mood has not changed. Side effects, such as nausea and jitteriness, come now.
2. 2

   Days to weeks

   Somatodendritic 5-HT1A autoreceptors, which at first damp serotonin neurons' firing, become less sensitive, so serotonin release rises. The drugs also shift how emotional information is processed, towards the positive, before mood lifts.
3. 3

   Weeks

   Gene expression, BDNF and the growth of new synapses in the hippocampus and cortex change. Mood improves over 2 to 6 weeks.

The monoamine hypothesis is too simple: monoamines rise within hours, while mood takes weeks, and lowering serotonin does not cause depression in healthy people. Glutamate, inflammation and neural plasticity are also involved, which esketamine's effect within hours supports.

How well they work

Across 21 antidepressants in a network meta-analysis of over 500 trials, every one beat placebo in acute depression, by a modest margin; other analyses find the margin larger in more severe depression. Amitriptyline was among the most effective, and agomelatine, escitalopram and vortioxetine among the best tolerated. About half of patients respond to the first drug, and about a third remit.

for mood to lift; no response by 4 weeks at a full dose means a change of plan

2 to 6weeksfor mood to lift; no response by 4 weeks at a full dose means a change of plan

at least, after remission, before stopping

6monthsat least, after remission, before stopping

the washout after an irreversible MAOI before another antidepressant, 3 before clomipramine or imipramine

2weeksthe washout after an irreversible MAOI before another antidepressant, 3 before clomipramine or imipramine

after fluoxetine before an MAOI is started

5weeksafter fluoxetine before an MAOI is started

The other actions

04Clinical indications

The antidepressants treat depression, the anxiety disorders and obsessive–compulsive disorder. In bipolar depression they are given only with a mood stabiliser, if at all, as they can bring on mania.

Choosing and starting

Switching

A switch is planned by what the drugs are and how long they last.

Stopping

Stopping an antidepressant suddenly, or missing doses of a short-acting one, can cause withdrawal (discontinuation) symptoms within a few days: dizziness, electric shock sensations, nausea, a flu-like feeling, vivid dreams, irritability, anxiety and low mood. They are commonest with paroxetine and venlafaxine and least with fluoxetine. Most are mild and pass in 1 to 2 weeks, but they can be severe and last for months in some.

The dose is tapered in steps over weeks, and often over months after long use, at a pace the patient agrees. Each step is a proportion of the last dose, so steps get smaller as the dose falls: at low doses a small cut removes a large share of the effect on the transporter. Liquid forms help at the end. Withdrawal comes on within days of a dose cut and eases within days of restarting, whereas relapse of depression builds up over weeks.

Esketamine and zuranolone

Esketamine nasal spray is licensed in the EU for treatment-resistant depression, in adults who have failed two antidepressants in the current episode, given with an SSRI or SNRI, and, since 2021, with an oral antidepressant as short-term treatment in a psychiatric emergency. It is given in a clinic, twice a week at first, with blood pressure measured before and about 40 minutes after each dose, then as needed, and the patient watched until stable; they do not drive until the next day, after a night's sleep. It is little used in the UK, where it has not been recommended for NHS use. Zuranolone is taken for 14 days, in the evening with food that contains fat, for postnatal depression; the patient must not drive for at least 12 hours after each dose, and it is ruled out in pregnancy.

05Adverse drug reactions

• Life-threatening
  Serotonin syndrome: agitation or confusion, sweating, fever, a fast pulse, dilated pupils and diarrhoea, with tremor, brisk reflexes and clonus, worse in the legs, within hours of a new drug or dose. Most dangerous with an MAOI combined with another serotonergic drug, or with linezolid or methylthioninium chloride; also tramadol, pethidine, fentanyl, triptans, lithium, St John's wort and MDMA. The drugs are stopped; fluids, cooling, benzodiazepines and cyproheptadine; intensive care if the temperature passes about 41 °C.
• Life-threatening
  Tricyclic overdose: drowsiness, coma and seizures, dilated pupils, a fast pulse, low blood pressure, and a wide QRS on the ECG that leads to ventricular arrhythmias. As little as 1 g of amitriptyline, a week's supply at a full dose, can kill. Sodium bicarbonate into a vein, and a benzodiazepine for seizures.
• Life-threatening
  Hypertensive crisis with an irreversible MAOI: tyramine-rich food (aged cheese, cured or fermented meat and fish, yeast extract, soy sauce, broad bean pods, draught beer) or sympathomimetics (pseudoephedrine, amphetamines, cocaine) cause a severe headache, palpitations and a very high blood pressure, with a risk of brain haemorrhage.
• Life-threatening
  Hyponatraemia, from inappropriate antidiuretic hormone secretion, mostly in the first month, in older people, women, those of low weight and on diuretics, with SSRIs and SNRIs most. Confusion, falls and seizures. A sodium below 125 mmol/L is dangerous.
• Life-threatening
  A long QT and torsades de pointes, with citalopram and escitalopram, dose-related, and with tricyclics, which also widen the QRS.
• Serious
  Suicidal thoughts and behaviour, early in treatment and under 25, with agitation and restlessness. In trials the risk rose against placebo under 25, was neutral from 25 to 64 and fell over 65; suicide risk is asked about at each review.
• Serious
  Bleeding, as SSRIs empty platelets of serotonin: bruising, nosebleeds and gut bleeding, several times likelier with an NSAID, aspirin or an anticoagulant, and a small rise in bleeding after childbirth. A proton pump inhibitor is added if the combination can't be avoided.
• Serious
  Mania or hypomania in bipolar disorder, likeliest with tricyclics and venlafaxine.
• Serious
  Seizures, with bupropion, tricyclics and in overdose; most antidepressants lower the threshold a little.
• Serious
  Liver injury with agomelatine, rarely failure; liver tests are taken before and during treatment, and it is stopped if transaminases pass 3 times the upper limit.
• Serious
  Raised blood pressure with venlafaxine at higher doses, duloxetine and esketamine.
• Serious
  Falls and fractures in older people, from dizziness, low blood pressure and low sodium.
• Serious
  Priapism with trazodone, an emergency.
• Serious
  Angle-closure glaucoma, from dilated pupils, with tricyclics and less often SSRIs and SNRIs.
• Serious
  Antimuscarinic toxicity from tricyclics: retention, constipation and delirium in older people.
• Serious
  Dissociation, sedation and misuse with esketamine, so it is given in a clinic.
• Serious
  Sexual dysfunction that lasts after stopping an SSRI or SNRI, rare; since 2019 EU product information warns of it.
• Serious
  Severe withdrawal, lasting weeks to months in some, after stopping suddenly.
• Serious
  Low neutrophils with mirtazapine and mianserin, rarely; a sore throat or fever means a blood count.

Monitoring

06Side effects

• Mild
  Nausea, indigestion and loose stools with SSRIs, SNRIs and vortioxetine, mostly in the first 2 weeks; taking the dose with food helps.
• Mild
  Anxiety, jitteriness and poor sleep in the first weeks of SSRIs and SNRIs; a lower starting dose helps.
• Mild
  Sexual dysfunction, low desire, delayed or absent orgasm and erectile problems, in up to half on SSRIs and SNRIs; less with mirtazapine, agomelatine, vortioxetine, bupropion and moclobemide.
• Mild
  Headache, sweating and yawning with SSRIs and SNRIs.
• Mild
  Sleepiness and weight gain with mirtazapine, trazodone and tricyclics.
• Mild
  Dry mouth, constipation, blurred vision and dizziness on standing with tricyclics.
• Mild
  Emotional blunting, feeling flat, on long-term SSRIs.
• Mild
  Insomnia and dry mouth with bupropion and MAOIs.
• Mild
  Dizziness, nausea, numbness and a feeling of detachment with esketamine, passing within about 2 hours.
• Mild
  Sleepiness and dizziness with zuranolone.

07Contraindications

• Contraindicated
  An MAOI with another antidepressant or serotonergic drug, including linezolid, methylthioninium chloride, tramadol, pethidine and triptans, and within the washout periods; and with sympathomimetics such as pseudoephedrine.
• Contraindicated
  Citalopram and escitalopram with a long QT, from birth or acquired, or with other drugs that lengthen it, such as antipsychotics, methadone, macrolides and antiarrhythmics.
• Contraindicated
  Tricyclics after a recent heart attack, with heart block or arrhythmias, in mania and in severe liver disease.
• Contraindicated
  Bupropion with epilepsy or past seizures, a brain tumour, anorexia or bulimia nervosa now or in the past, sudden withdrawal from alcohol or benzodiazepines, severe cirrhosis, a history of bipolar disorder, or an MAOI.
• Contraindicated
  Agomelatine with liver disease or transaminases over 3 times the upper limit, and with strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin).
• Contraindicated
  Duloxetine with liver disease, severe kidney disease, fluvoxamine or ciprofloxacin, or started with uncontrolled high blood pressure.
• Contraindicated
  Esketamine where a rise in blood pressure or brain pressure is dangerous: an aneurysm, a past brain haemorrhage, or a heart attack or other cardiovascular event in the last 6 weeks.
• Avoid
  Tricyclics where there is a risk of overdose, above all dosulepin and amitriptyline, and in heart disease and older people, where an SSRI is preferred.
• Avoid
  Paroxetine, fluoxetine or bupropion with tamoxifen, which they make less effective by blocking CYP2D6; venlafaxine, mirtazapine, citalopram and escitalopram barely affect it.
• Avoid
  An antidepressant alone in bipolar disorder, without a mood stabiliser or antipsychotic.
• Avoid
  Venlafaxine with uncontrolled high blood pressure or a high risk of serious arrhythmia.
• Avoid
  Agomelatine at 75 years and over, in whom it hasn't been shown to work.
• Caution
  NSAIDs, aspirin, anticoagulants and antiplatelets with SSRIs and SNRIs, for bleeding; a proton pump inhibitor is added, or mirtazapine chosen.
• Caution
  Older people, diuretics and proton pump inhibitors, for hyponatraemia; the sodium is checked.
• Caution
  Other serotonergic drugs: tramadol, triptans, lithium, St John's wort, linezolid, fentanyl.
• Caution
  Enzyme interactions: fluvoxamine raises clozapine, olanzapine, theophylline and caffeine; fluoxetine and paroxetine raise tricyclics, risperidone, aripiprazole and metoprolol; St John's wort lowers the pill, warfarin and many others.
• Caution
  Epilepsy, diabetes, glaucoma and heart disease; SSRIs can change the blood sugar, and tricyclics need an ECG first in heart disease.
• Caution
  People at risk of suicide: a drug safe in overdose, in small supplies, and an early review.
• Caution
  Kidney and liver disease: lower doses or another drug, with duloxetine, venlafaxine and the tricyclics above all.

08Pregnancy and lactation

• Caution
  SSRIs in pregnancy. Large studies have not found that they cause malformations overall, while untreated depression harms mother and baby, so a woman who needs one usually continues it, sertraline being the one most studied. Small risks remain: a slight rise in persistent pulmonary hypertension of the newborn, a newborn adaptation syndrome (jitteriness, poor feeding, fast breathing) in up to a third, usually mild and brief, and a little more bleeding after birth when taken in the last month.
• Caution
  Paroxetine in early pregnancy. Its product information cites a small rise in heart defects, under 2 in 100 babies against about 1 in 100, but most studies do not support a rise with any SSRI, and UKTIS ranks none safer than another. It is not usually the one to start in pregnancy, but a woman well on it is not switched hastily.
• Caution
  SNRIs, tricyclics and mirtazapine in pregnancy, with no clear rise in malformations; the newborn is watched for withdrawal and, after venlafaxine, the mother's blood pressure.
• Avoid
  MAOIs, agomelatine, vortioxetine, bupropion and esketamine in pregnancy, for want of data and, with MAOIs, the risk of a hypertensive crisis.
• Contraindicated
  Zuranolone in pregnancy, which harmed the young in animal studies; women who could become pregnant use effective contraception during the course and for 7 days after it.
• Compatible
  Breastfeeding with sertraline, paroxetine, citalopram, escitalopram, venlafaxine, mirtazapine, amitriptyline or nortriptyline, rated very low risk by e-lactancia. Sertraline and paroxetine reach the baby in the smallest amounts; citalopram and venlafaxine reach more, so a newborn or premature baby is watched for sleepiness, poor feeding and irritability. Most licences advise against breastfeeding or weighing it up.
• Caution
  Breastfeeding with fluoxetine, whose long-lived metabolite reaches higher levels in the baby, above all a newborn or premature one, who is watched. A woman well on it is usually not switched.
• Caution
  Breastfeeding with agomelatine, bupropion, esketamine or zuranolone, probably compatible by e-lactancia, with little data; their licences say to weigh it up, and zuranolone's to stop breastfeeding during the course unless the benefit outweighs the risk.
• Avoid
  Breastfeeding with phenelzine or isocarboxazid, for want of data; moclobemide is rated very low risk.
• Contraindicated
  Breastfeeding with doxepin, whose metabolite has slowed a baby's breathing; e-lactancia rates it incompatible.