Serious harms

Sertraline is prescribed for depression and for panic, social anxiety, obsessive–compulsive, post-traumatic stress and premenstrual dysphoric disorders 1.

ConditionHow oftenWho is at riskSource
Suicidal thoughts and behaviourShort-term antidepressant trials: 14 more per 1000 than placebo under 18, 5 more at 18 to 24Under 252
Serotonin syndrome, potentially life-threateningNot statedOther serotonergic drugs; MAO inhibitors contraindicated2
Bleeding, up to life-threateningUpper gastrointestinal, 1 year, aged 65 or older: 0.44% against 0.42% untreatedAspirin, NSAIDs, anticoagulants may add23
Intracranial haemorrhageSSRIs: 6.7 per 100,000 person-years above tricyclicsFirst 30 days of use4
Postpartum haemorrhageUnder two-fold increaseMonth before delivery5
Hyponatraemia, deaths reported1 year, aged 65 or older: 0.29% on sertraline and untreated, 0.44% on SSRIsOlder age, diuretics, volume depletion23
Falls, fractures, seizures1 year: 5.57%, 2.80%, 0.55%, against 3.46%, 1.76%, 0.21% untreated (observational)Aged 65 or older6
Torsade de pointesPostmarketing reportsPimozide, contraindicated; QT-prolonging drugs2
Mania or hypomania0.4% in trialsBipolar disorder2
Angle-closure glaucomaNot statedUntreated narrow angles2
Liver failure, pancreatitis, agranulocytosis, aplastic anaemia, thrombocytopenia, Stevens–Johnson syndrome, toxic epidermal necrolysis, reversible cerebral vasoconstriction, pulmonary hypertension, rhabdomyolysis, maculopathy, sexual dysfunction lasting after stoppingPostmarketing reportsNot stated27
Newborn toxicity or withdrawal, needing respiratory supportPostmarketing reportsLate third-trimester exposure2
Newborn pulmonary hypertension2.9 to 3.5 extra per 1000 infantsLate-pregnancy exposure8
Severe withdrawal symptoms2.8% against 0.6% after placeboStopping, particularly abruptly92

In regulators’ clinical study reports, 27 suicide attempts and 32 ideation events had been coded as emotional lability or worsening depression; in 16 sertraline trials, a terminology unable to code akathisia or suicidal ideation was used 10.

MAO inhibitors raise serotonin syndrome risk by impairing serotonin breakdown 2. Sertraline blocks serotonin uptake into platelets, and impaired platelet aggregation is the proposed cause of bleeding 15. Hyponatraemia is often attributed to inappropriate antidiuretic hormone secretion 2.

In older people, most risks were highest in the first 28 days after starting and after stopping; confounding by indication is possible 6. In a randomised trial of fluoxetine, another SSRI, fractures were recorded in 45 of 1564 against 23 of 1563 stroke patients over 6 months, about 1 extra per 71 treated 11. Among women with depression, the adjusted odds ratio for newborn pulmonary hypertension after late-pregnancy SSRI use was 1.10 (95% CI 0.94 to 1.29) 12. Transient, asymptomatic aminotransferase rises and rare clinically apparent liver injury are linked to sertraline 13.

Other pathways it affects

The transporter that sertraline blocks also moves serotonin in the gut lining and into blood platelets 1415.

TissueSerotonin proteinMeasured in people
Gut liningSERT; 5-HT3 and 5-HT4 receptors 14Nausea 26% against 12% on placebo, diarrhoea 20% against 10% 1
PlateletsSERT fills dense granules; 5-HT2A 1514Bleeding, above
Bone, heart, pulmonary artery, liver, kidney5-HT2B; roles inferred from animals 14Fractures and pulmonary hypertension, above

Shown in mice: 6 weeks of fluoxetine caused bone loss through raised sympathetic output, prevented by propranolol 16.

Measured in people: new weight gain of 5% or more was recorded at 11.2 against 8.1 per 100 person-years with and without antidepressants, 1 extra per 59 patient-years 17. Ejaculation failure was reported in 8% of men against 1% on placebo, rates described in the label as possibly underestimated 2.

What it is for and how it works

Sertraline blocks the transporter that returns serotonin, a signalling molecule, into the nerve cell that released it 151.

SERT (SLC6A4) moves serotonin back with Na+ in exchange for K+, and MAO-A then deaminates it 15.

Serotonin synthesis, release, reuptake and breakdownSerotonergic neuron cytosol, synaptic vesicles, synaptic cleft and mitochondrial outer membrane
  1. L-Tryptophan
  2. Tryptophan 5-hydroxylase 2 (TPH2)Fe2+, O2, Tetrahydrobiopterin to 4a-hydroxytetrahydrobiopterinRate-limiting step; TPH2 is the neuron-specific isoform
  3. 5-Hydroxy-L-tryptophan
  4. Aromatic L-amino acid decarboxylase (DDC)Pyridoxal 5'-phosphateReleases CO2
  5. Serotonin
  6. Vesicular monoamine transporter 2 (VMAT2, SLC18A2)2 H+ leave the vesicle per serotoninReserpineTetrabenazineThe V-type proton ATPase builds the proton gradient
  7. Vesicular serotonin
  8. several stepsRelease by exocytosis
  9. Synaptic serotonin
  10. Serotonin transporter (SERT, SLC6A4)1 Na+ in, 1 K+ outSertralineThe same transporter loads platelets with serotonin from plasma
  11. Presynaptic cytosolic serotonin
  12. Monoamine oxidase A (MAO-A)FAD, O2Monoamine oxidase inhibitorsMitochondrial outer membrane; also forms H2O2 and NH4+
  13. 5-Hydroxyindole-3-acetaldehyde
  14. Aldehyde dehydrogenaseNAD+ to NADHShown experimentally for ALDH9A1
  15. 5-Hydroxyindole-3-acetic acid (5-HIAA)

In the body

Half of the sertraline in blood is cleared in about a day 1.

CYP2C19 and CYP2B6 are regarded as the most relevant metabolising enzymes 2122. Exposure was about threefold higher in 10 patients with mild hepatic impairment 1. Sertraline inhibits CYP2D6 and may raise exposure to flecainide, propafenone and metoprolol 1.

Genetic variation

Inherited enzyme variants alter the amount of sertraline in the blood 21.

Serum sertraline was 2.68-fold higher in CYP2C19 poor metabolisers among 1202 patients 21.

Benefit against harm

On average, people improved slightly more on antidepressants than on placebo 24.

GroupBenefitSerious harm
Depression, acute placebo-controlled trialsLarge response 24.5% against 9.6% in 232 trials, 1 per 6.7 treated 24Serious adverse events 2.7% against 2.1% in 44 SSRI trials, 1 per 138 25
Aged 65 or olderSuicidal thoughts or behaviour, 6 fewer per 1000 2Death in 1 year, 10.20% against 7.04% untreated, observational 6

The mean difference was 1.75 Hamilton points, 1.1 at a baseline of 16 and 2.5 at 29.6 24. Drug companies funded 409 of 522 trials in a network meta-analysis of 21 antidepressants 26. In the NIHR-funded PANDA trial of 655 primary-care adults, depression scores on sertraline were not significantly lower at 6 weeks, 13% lower at 12 weeks, and anxiety scores 21% lower at 6 weeks 27.

Without the medicine

Exercise and talking therapy were compared with antidepressants in independent randomised trials 2829.

In SMILE, 16-week remission was 45% with supervised exercise, 40% at home, 47% with sertraline and 31% with placebo (p=0.057), among 202 adults 28. In five trials of 660 patients, response was 44.2% with second-generation antidepressants and 45.5% with cognitive behavioural therapy 29.

How the recommendations were set

Selective publication of SSRI trials was documented in regulators’ files 30.

Mean scores were missing from FDA reviews for four non-significant sertraline trials, with 486 patients, 38% of those in sertraline trials 31.

Stopping

Dizziness, electric-shock sensations, anxiety and seizures have been reported after stopping, particularly abruptly; gradual reduction is recommended 2.

Across 79 studies, discontinuation symptoms were recorded in 31% after stopping an antidepressant and 17% after placebo, 8 percentage points more in randomised trials; in 5 sertraline studies, 18% 9. In ANTLER, 56% of 240 people tapered to placebo over 1 to 2 months relapsed within 52 weeks, against 39% of 238 who continued, and withdrawal scores were higher 34. In a Cochrane review of 33 trials, most tapers were 4 weeks or shorter and withdrawal was generally not assessed 35.

A prescription is changed together with the prescriber.