Ranking
Safest Antidepressants 2026
Every antidepressant we score, from the SSRIs sertraline and escitalopram to the SNRIs, mirtazapine, vortioxetine and the tricyclics amitriptyline and nortriptyline. Each score rates the medicine as prescribed for an average adult, on serious side effects, overdose margin, interactions, dependence and withdrawal, regulatory warnings and track record. The right antidepressant for you depends on your health, your other medicines, your age and pregnancy, and none should be stopped suddenly.
Updated · Scores update with each page
The ranking
Sertraline
Sertraline (Zoloft, Lustral) is one of the most prescribed antidepressants and one of the better tolerated. Nausea and sexual side effects are common, under-25s need close watching early on, and it interacts with other serotonin drugs and blood thinners.
Score 72, grade BEscitalopram
Escitalopram (Lexapro, Cipralex) is among the better tolerated antidepressants and is not addictive. The catches are the class boxed warning for young people, discontinuation symptoms if stopped suddenly, and a small dose-related effect on the QT interval that limits the dose in older adults.
Score 71, grade BVortioxetine
Vortioxetine (Trintellix in the US, Brintellix in the UK and EU) is a newer antidepressant for major depression. It is not a controlled drug. Nausea is common early on, but sexual side effects, weight gain and withdrawal are less of a problem than with many SSRIs. Its record is only about 13 years long.
Score 71, grade BFluoxetine
Fluoxetine (Prozac) is the original SSRI and still one of the most used. Its very long half-life makes stopping easier but interactions last for weeks after the last dose. Under-25s need close watching early on, and it is less forgiving in overdose than sertraline.
Score 70, grade BCitalopram
Citalopram (Celexa, Cipramil) is a widely used SSRI that is not addictive and suits many adults with depression. Its main catch is a dose-related effect on heart rhythm, which led regulators in 2011 to cap the dose at 40 mg (20 mg for older adults) and makes overdoses more dangerous than with sertraline.
Score 67, grade CTrazodone
Trazodone is a 1981 antidepressant now prescribed mostly at low doses for sleep, an unapproved use. It is not controlled and rarely misused, but drowsiness and dizziness are common, and the label warns of priapism, heart rhythm problems, serotonin syndrome and suicidal thoughts in young people.
Score 67, grade CDuloxetine
Duloxetine (Cymbalta) is an SNRI for depression, anxiety and chronic pain such as diabetic nerve pain. It is not addictive and rarely fatal in overdose on its own. The catches are early nausea, symptoms on stopping, rare serious liver injury and many interactions.
Score 66, grade CMirtazapine
Mirtazapine (Remeron) is an antidepressant taken at night that helps sleep and appetite and rarely causes sexual problems. It is not a controlled drug. It scores below most SSRIs because more than half of users in US trials reported sleepiness, weight gain is common, and overdoses are more often fatal than with SSRIs.
Score 65, grade CDesvenlafaxine
Desvenlafaxine (Pristiq) is an SNRI for depression and the main active form of venlafaxine. It is not a controlled drug. At the standard 50 mg dose few people stop it for side effects and it has few drug interactions, but it can raise blood pressure and withdrawal symptoms are frequent and sometimes severe.
Score 63, grade CParoxetine
Paroxetine (Paxil, Seroxat) is an effective, non-addictive SSRI for depression and anxiety disorders. It scores below sertraline because withdrawal is more severe, it interacts with many common medicines, and early-pregnancy use is linked to heart defects.
Score 63, grade CBupropion
Bupropion (Wellbutrin, Zyban) works differently from SSRIs and spares sex drive and weight. The trade-offs are a dose-related seizure risk, higher blood pressure, many interactions through the liver and an overdose profile much more dangerous than SSRIs, with seizures in about a third of cases.
Score 60, grade CVenlafaxine
Venlafaxine (Effexor XR, Efexor XL) is an SNRI widely used for depression and anxiety, often after an SSRI has not worked. It is not a controlled drug. It scores lower than SSRIs because withdrawal symptoms are common and can be severe, it raises blood pressure at higher doses, and overdoses are more often fatal.
Score 59, grade CNortriptyline
Nortriptyline is a tricyclic antidepressant, the main active form of amitriptyline, and in the UK it is also used at low doses for nerve pain. It is less anticholinergic than amitriptyline and is not addictive. It scores low because overdoses are dangerous, it slows heart conduction and many drugs raise its levels.
Score 54, grade DAmitriptyline
Amitriptyline is a tricyclic antidepressant now often used at low doses for nerve pain and migraine prevention. It is not addictive. It scores low because drowsiness and dry mouth are common, it affects heart rhythm, and an overdose of a few weeks' supply can kill.
Score 52, grade D
Which medicines are on this list
The rule is the main licensed use: a medicine is here when it is approved first of all as an antidepressant. That covers the SSRIs sertraline, escitalopram, citalopram, fluoxetine and paroxetine; the SNRIs duloxetine, venlafaxine and desvenlafaxine; bupropion, which acts on dopamine and noradrenaline; mirtazapine, which blocks certain receptors instead of serotonin reuptake; vortioxetine, which blocks serotonin reuptake and acts on several serotonin receptors; trazodone, approved for depression in 1981 but now prescribed mostly at low doses for sleep; and the tricyclics amitriptyline, approved for depression in 1961 and now also widely taken at low doses for nerve pain and migraine, and nortriptyline, its main active form in the body, approved in 1964 and also used at low doses for nerve pain in the UK.
Quetiapine is left out because it is an antipsychotic, even though it is approved for bipolar depression and, in its XR form, as an add-on for major depression. So are lithium and lamotrigine, which prevent mood episodes in bipolar disorder. Tianeptine and St John's wort are on our supplements pages, because that is how they are sold in the US.
How the order is built
Each medicine is scored on six factors. Serious side effects at normal doses count for 30%, the Overdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary for 20%, interactions and dependence (which for these drugs mostly means withdrawal on stopping) for 15% each, and regulatory warnings and track record for 10% each. The rubrics are on how we score medications.
The list is those scores sorted from the highest down, and it moves when we update a page, so this text does not quote scores. The scores span a wide range, from the SSRIs near the top to the tricyclics amitriptyline and nortriptyline at the bottom, but every drug here shares the same US Boxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary on suicidal thoughts in people under 25, and in October 2026 the MHRA announced new UK leaflet warnings for antidepressants, including on sexual problems that can last after stopping.
What the SSRIs near the top have in common
None is addictive, and sertraline and escitalopram have the widest overdose margins on this list. The sertraline label records a person who survived 13.5 g, and escitalopram trial overdoses of up to 600 mg caused no deaths. Fluoxetine's very long half-life makes stopping gentler, though its interactions last for weeks after the last dose. Citalopram sits a little lower because it lengthens the QT prolongationA delay in the heart's electrical recovery between beats, seen on an ECG. Some medicines cause it, and in rare cases it leads to a serious heart rhythm problem.More in the glossary on an ECG in proportion to dose, which led regulators in 2011 to cap it at 40 mg a day, and 20 mg in older adults. Vortioxetine sits with this group: it is not addictive, its long half-life makes stopping easier, and overdoses reported so far mostly caused nausea and vomiting, but its record goes back only to 2013.
Why some are lower
The lower scores mostly come from overdose and withdrawal. The two tricyclics are the clearest case: the UK amitriptyline label warns of severe toxicity from 750 mg in an adult, about 30 tablets of 25 mg, the nortriptyline label says 50 mg can be an overdose in a child, and in England and Wales overdoses of tricyclics were far more often fatal than those of SSRIs. Both also slow electrical conduction in the heart. Mirtazapine causes sleepiness and weight gain, and in 2024 it was named on more drug-poisoning death certificates in England and Wales than any other single antidepressant, almost always alongside other drugs or alcohol. Bupropion causes seizures in about a third of overdoses, and in US poison centre data on teenagers it led to a serious outcome far more often than SSRIs did. Venlafaxine overdoses were about five times as likely to be fatal as SSRI overdoses in a study of England and Wales, and its short half-life makes withdrawal common and sometimes severe. Desvenlafaxine, the active form of venlafaxine, shares its blood pressure effects and hard withdrawal. Paroxetine is the SSRI that sits lower, because withdrawal is often severe, it strongly blocks the liver enzyme CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary and it carries the pregnancy warning. Duloxetine carries a rare risk of serious Drug-induced liver injuryLiver damage caused by a medicine, herbal product or supplement. It is usually rare and unpredictable, but it can be serious.More in the glossary, and trazodone a rare risk of priapism and heart rhythm problems. A lower place is not a verdict on the medicine: bupropion spares weight and sex drive, mirtazapine helps sleep and rarely affects sex drive, venlafaxine is often used when an SSRI has not worked, and low doses of amitriptyline or nortriptyline for pain are usually well tolerated.
What the score does not tell you
The score rates side effects and risks for an average adult. It does not measure how well a medicine treats depression, and it cannot weigh your heart, liver, age, pregnancy or the other medicines you take. Do not start, stop or switch an antidepressant because of this list. Never stop one abruptly: talk to your doctor or pharmacist, who can plan a gradual taper if a change is right for you. If you have thoughts of harming yourself, contact your doctor or an emergency service straight away.
Questions
What is the safest antidepressant?
No single one is safest for everyone. The SSRIs sertraline, escitalopram and fluoxetine, with the newer vortioxetine, form the group nearest the top, because they are not addictive and are far less dangerous in overdose than tricyclics such as amitriptyline. The SSRIs have decades of data, while vortioxetine has been on the market only since 2013. Each still carries the Boxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary on suicidal thoughts in people under 25. Your doctor will weigh your other medicines, heart, age and pregnancy plans before choosing.
Which antidepressant has the fewest side effects?
Trials are not directly comparable, but escitalopram's figures are low for an antidepressant. In its depression trials, 6% stopped because of side effects against 2% on placebo, and at 10 mg the dropout rate was not significantly different from placebo. In the label trials of citalopram, 16% stopped against 8%, and for venlafaxine 12% against 4%. Nausea often fades within weeks, while sexual side effects are the ones most likely to last.
Which antidepressant does not cause weight gain?
Of the antidepressants we score, bupropion is the one least linked to weight gain, because it acts on dopamine and noradrenaline rather than serotonin. In the trials of its XL form for seasonal depression, 23% lost 5 lb or more against 11% on placebo, and sexual side effects are also uncommon. Fluoxetine reduced appetite in 11% of people in its trials, against 2% on placebo. Mirtazapine is the one most linked to weight gain. In its US trials 7.5% gained at least 7% of their body weight, against none on placebo. Bupropion has its own risks, including seizures, so talk to your doctor before switching.
Can I stop taking antidepressants suddenly?
No. Stopping suddenly can cause discontinuation symptoms such as dizziness, electric-shock sensations, irritability, nausea and insomnia, which for some people last weeks. They are more common with short-acting drugs such as venlafaxine, desvenlafaxine and duloxetine, and are often severe with paroxetine. They are milder with fluoxetine and vortioxetine, which leave the body slowly; vortioxetine's half-life is about 66 hours. Plan any reduction with your prescriber, who may taper the dose over weeks or months.
Are antidepressants addictive?
None of the antidepressants on this list is a Controlled substanceA medicine or drug that the law restricts because it can be misused or cause dependence. Countries group them into schedules or classes.More in the glossary, and they do not cause cravings, a high or a need for ever higher doses. The body does adapt to them, which is why stopping causes discontinuation symptoms. Bupropion is the exception on misuse, as seizures and deaths have been reported after people snorted or injected crushed tablets.
Which antidepressant is safest in pregnancy?
Sertraline is one of the antidepressants used most in pregnancy and breastfeeding. Paroxetine is the one with a US label warning on heart defects after use in the first three months. The MHRA flagged a possible small rise in heart defects with fluoxetine in the first trimester in 2014, and warned in 2021 of a small extra risk of heavy bleeding after birth with SSRIs or SNRIs taken in the month before delivery. Untreated depression also carries risks, so do not stop on your own; talk to your doctor or midwife.
Why do antidepressants carry a warning about suicidal thoughts?
Since 2004 every antidepressant in the US has carried a Boxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary, extended to under-25s in 2007. In pooled short trials, antidepressants led to 14 more cases of suicidal thoughts or behaviour per 1,000 children and teenagers treated and 5 more per 1,000 aged 18 to 24, but fewer in adults over 25. The warning is about close watching in the first months and after dose changes, not about avoiding treatment.