MHRA guidance (2014): Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs): use and safety

There is a risk of suicidal behaviour with the use of any SSRI and SNRI, particularly when used by children, adolescents or young adults. Refer to Treatment of unipolar depression, for further guidance.

In 2008, a meta-analysis of data on antidepressants, including SSRIs and SNRIs, was completed by the Food and Drug Agency (FDA) in the USA. The results of this analysis were reviewed in both the UK and in Europe.

The UK/EU review concluded that the risk of suicidal acts and behaviour is increased with the use of SSRIs or SNRIs in young people aged up to 25 years. The risks of sertraline, citalopram, escitalopram, paroxetine, venlafaxine, and mirtazapine outweigh the benefits when used in children and adolescents with depression and should not be used in this patient group.

The risk of suicide is greatest in the early stages of SSRI treatment. This may be due to the fact that SSRIs and SNRIs need to be taken for a few weeks before they are effective in treating depression (which is itself associated with an increased risk of suicidal behaviour).

All SSRIs and SNRIs may be associated with withdrawal reactions on stopping or reducing treatment. Withdrawal reactions are less severe when the dose is gradually decreased or 'tapered off' over several weeks. The most commonly experienced withdrawal reactions are: dizziness, numbness and tingling, gastrointestinal disturbances (particularly nausea and vomiting), headache, sweating, anxiety, sleep disturbances. See "Stopping and switching between antidepressants", here.

SSRIs and SNRIs cross the placenta in pregnant women and have the potential to affect the unborn foetus. Pregnant women should only use SSRIs or SNRIs after discussing any potential risks to their unborn child with their doctor. See "Depression in pregnancy and the postnatal period", here. The UK Teratology Information Service (UKTIS) provides a national service on all aspects of the toxicity of drugs and chemicals in pregnancy (Tel: 0344 892 0909), and provides the 'best use of medicines in pregnancy' (bumps) website for supportive information relating to individual treatments.

SSRIs have been associated with a small increased risk of fractures.

MHRA Drug Safety Update (December 2014)

Citalopram and escitalopram: QT interval prolongation

Citalopram and escitalopram have been found to prolong the QT interval in a dose dependent manner. The maximum daily doses for citalopram and escitalopram are restricted – see individual drug entries.

Citalopram and escitalopram are contraindicated in patients at greatest risk of QT interval prolongation, such as those with:

• Congenital long QT syndrome
• Known pre-existing QT interval prolongation
• In combination with other medicines that prolong the QT interval; these include (but note that this is not an exhaustive list)
  • Class IA and III antiarrhythmics (e.g. amiodarone, dronedarone, quinidine)
  • Antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol)
  • Tricyclic antidepressants (TCAs)
  • Some antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, antimalaria treatment—particularly halofantrine)
  • Some antihistamines (astemizole, mizolastine)
  • Some antiretrovirals (e.g. ritonavir, saquinavir, lopinavir)

Patients taking concomitant medications known to increase plasma levels of escitalopram and citalopram may require a dose reduction. Drugs known to increase plasma concentrations of escitalopram and citalopram include some antiretroviral medications, and omeprazole and cimetidine.

The balance of benefits and risks of citalopram and escitalopram should be considered carefully, particularly at higher doses, in patients with pre-existing risk factors for QT interval prolongation, for example:

• Congestive heart failure
• Recent myocardial infarction
• Bradyarrhythmias or predisposition to hypokalaemia or hypomagnesaemia because of concomitant illness or medicines

The MHRA suggest the following monitoring recommendations:

• In patients with cardiac disease, an ECG review should be considered before treatment with citalopram and escitalopram
• Electrolyte disturbances (eg, hypokalaemia and hypomagnesaemia) should be corrected before treatment with citalopram and escitalopram. Monitoring of serum magnesium is advised, particularly in elderly patients, who may be taking diuretics or proton pump inhibitors
• If cardiovascular symptoms, such as palpitations, vertigo, syncope, or seizures develop during treatment, cardiac evaluation including an ECG should be undertaken to exclude a possible malignant cardiac arrhythmia.
• If QTc interval is >500 milliseconds, treatment should be withdrawn gradually.
• If QTc interval duration is between 480 milliseconds and 500 milliseconds, the balance of benefits and risks of continued treatment should be carefully considered, alongside options for dose reduction or gradual withdrawal

For further details refer to BNF, individual manufacturer Summary of Product Characteristics and see also Drugs that prolong the QT interval, formulary guidance.

MHRA Drug Safety Update (January 2021): SSRI/SNRI antidepressant medicines: small increased risk of postpartum haemorrhage when used in the month before delivery

• SSRIs and SNRIs are known to increase bleeding risks due to their effect on platelet function. Data from observational studies suggest that the use of SSRI/SNRI antidepressants during the month before delivery may result in a small increased risk of postpartum haemorrhage.
• Prescribers should consider this risk in the context of an individual patient’s bleeding and thrombotic risk assessment during the peripartum period and the benefits of antidepressants for the patient’s mental health during this time.

Sertraline

• Tablets 50mg, 100mg (£1.10 = 100mg daily)

Indications

• Generalised anxiety disorder (unlicensed indication)
• Unipolar depression
• Panic disorder
• Post-traumatic stress disorder
• Social anxiety disorder

Fluoxetine

• Capsules 20mg (£0.79 = 20mg daily)
• Oral solution 20mg/5ml (£6.73 = 70ml)
• Dispersible tablets sugar free (£3.44 = 20mg daily)

Indications

• Unipolar depression

Notes

1. Consider the long half-life of fluoxetine when adjusting dosage (or in overdosage).
2. Fluoxetine is licensed for children aged 8 years and above. Antidepressants should only be prescribed in children and adolescents following assessment and diagnosis by a child and adolescent psychiatrist. Refer to Depression in children and adolescents, here, for further guidance.
3. Fluoxetine 20mg dispersible tablets may be divided in to equal halves for administration of a 10mg dose.

Escitalopram

• Tablets 5mg, 10mg, 20mg (£1.11 = 10mg daily)

Indications

• Unipolar depression
• Generalised anxiety disorder (specialist)

Notes

1. Escitalopram maximum adult daily dose: 20mg daily.
2. In adults over 65 years of age and adults with hepatic impairment the maximum daily dose of escitalopram is 10mg daily.
3. Escitalopram is contraindicated in patients at greatest risk of QT interval prolongation. See guidance above

Citalopram

• Tablets 10mg, 20mg, 40mg (£0.81 = 20mg daily)
• Oral drops sugar free 40mg/ml (£14.89 = 15ml)

Indications

• Unipolar depression
• Panic disorder

Notes

1. Citalopram maximum adult daily dose: 40mg daily.
2. In adults over 65 years of age and adults with hepatic impairment the maximum daily dose is 20mg daily
3. 4 oral drops (8mg) is equivalent in therapeutic effect to 10mg tablet
4. Citalopram oral drops should be reserved for use in patients with swallowing difficulties
5. Citalopram is contraindicated in patients at greatest risk of QT interval prolongation. See guidance above

Vortioxetine

• Tablets 5mg, 10mg, 20mg (£27.72 all strengths = one daily)

Indications

• Major depression
• Formulary guidance on the management of unipolar depression can be accessed here

Notes

1. NICE TA367: Vortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to two antidepressants within the current episode. (November 2015).