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 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 fetus. 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.

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.

Duloxetine

• Gastro-resistant capsules 30mg, 60mg (£2.56 = 60mg daily)
• Gastro-resistant capsules 20mg, 40mg (£6.64 = 40mg twice daily)

Indications

• Diabetic neuropathy:
  • 60 mg once daily, discontinue if inadequate response after 2 months; review treatment at least every 3 months; dose can be increased if necessary up to a maximum of 120 mg daily in divided doses.
• Moderate to severe stress urinary incontinence in women (see note 1):
  • 40 mg twice daily, alternatively 20 mg twice daily for 2 weeks then increased to 40 mg twice daily.

Notes

1. Duloxetine for urinary incontinence in women is only to be used as part of a programme that includes pelvic floor exercises. Patients should be informed its use for this indication has not been evaluated for longer than 3 months in placebo-controlled studies, assess for benefit and tolerability after 2-4 weeks
2. Prescribers should be aware that the 30mg and 60mg capsules are licensed for diabetic peripheral neuropathic pain, treatment of major depressive disorder (non-formulary), and generalised anxiety disorder (non-formulary). The 20mg and 40mg capsules are licensed for women for the treatment of moderate to severe stress urinary incontinence.
3. MHRA 2014: Duloxetine: marketed as Cymbalta▼ and Yentreve▼ for different disorders
   1. The benefit to the patient of taking duloxetine for diabetic neuropathy should be assessed by a doctor at least every 3 months.
   2. Duloxetine should not be prescribed to patients who have: liver disease leading to impaired liver function; severe kidney impairment; uncontrolled hypertension.
   3. Cases of suicidal ideation and suicidal behaviour have been reported during treatment with duloxetine or shortly after stopping treatment. Patients and caregivers should monitor and report to their doctor any distressing thoughts or feelings, signs of depression, suicidal behaviour or ideation, or thoughts of self-harm if they occur at any time during or after treatment.
   4. Patients should avoid abrupt withdrawal of treatment. Healthcare professionals should prescribe gradually reduced doses over at least 1–2 weeks to minimise withdrawal reactions. If a patient has intolerable symptoms after decreasing or stopping treatment, the drug may be re-prescribed or the dose increased; any subsequent reductions in dose may be done more gradually.

Mirtazapine

• Tablets 15mg, 30mg, 45mg (£1.41 = 30mg daily)
• Orodispersible tablets 15mg, 30mg, 45mg (£1.73 = 30mg daily)
• Oral solution sugar free 15mg/ml (£131.04 = 66ml)

Indications

• Unipolar depression
• Post-traumatic stress disorder (unlicensed indication)

Notes

1. Mirtazapine oral solution is only for use via enteral feeding tubes, orodispersible tablets will block the tube.
2. Mirtazapine appears to be safer in overdose and is thought to cause less insomnia, anxiety and agitation. Sexual dysfunction is rare and the likelihood of drug interactions is low. Weight gain may be significant.
3. Reversible blood dyscrasias, including agranulocytosis, have been reported infrequently in people taking mirtazapine. This usually occurs after 4–6 weeks of treatment and is reversible after stopping treatment. Patients should be advised to report any fever, sore throat, stomatitis or other signs of infection during treatment. Blood count should be performed and the drug stopped immediately if blood dyscrasia suspected.
4. Drowsiness often occurs during the first few weeks of treatment. This effect is not dose-related and should not prompt a reduction in dose (as this will lead to reduced efficacy). In most people drowsiness is transient.

Venlafaxine

• Modified-release capsules 37.5mg, 75mg, 150mg (£2.83 = 75mg daily)
• Modified-release capsules 225mg (click here for preferred brand)
• Tablets 37.5mg, 75mg (£3.93 = 75mg daily)

Indications

• Unipolar depression
• Generalised anxiety disorder
• Social anxiety disorder

Notes

1. Compared with other equally effective antidepressants recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose.
2. Modified-release capsules should routinely be offered since they provide more consistent blood levels than immediate-release venlafaxine
3. Doses below 150mg of venlafaxine produce a predominantly Selective Serotonin Re-uptake Inhibitor (SSRI) action. If the patient had no response to an SSRI, doses of at least 150mg venlafaxine per day may be required. The dose should be titrated gradually
4. Treatment with venlafaxine is associated with a higher risk of withdrawal effects than other antidepressants. When stopping the dose should be reduced over several weeks.
5. MHRA 2014: Venlafaxine and the risks associated with overdose:
   1. Specialist supervision is needed for severely depressed or hospitalised patients who require venlafaxine doses of 300 mg daily or more
   2. Cardiac contra-indications are more targeted towards high-risk groups
   3. As previously, patients with uncontrolled hypertension should not take venlafaxine, and blood pressure monitoring is recommended for all patients
   4. Concomitant SSRI use should be restricted to specialist use
   5. Other drug interactions are a possibility, particularly CYP3A4 inhibitors and CYP2D6 inhibitors
   6. These interacting drugs should only be prescribed when strictly indicated.
6. Where a preferred brand is recommended for a particular presentation, prescribing by brand helps ensure cost-efficient use of local NHS resources (see preferred brand link above)

Esketamine

• NICE TA854: Esketamine nasal spray (Spravato) with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is not recommended, within its marketing authorisation, for treatment-resistant depression that has not responded to at least 2 difference antidepressants in the current moderate to severe depressive episode in adults (December 2022).