Guidance

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

Published 18 December 2014

This page was published in 2014 and remains online only as a historical record.  For updated information about these medicines, please consult the relevant Summary of Product Characteristics and Patient Information Leaflet on the MHRA’s products page.

1. Overview

1.1 Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of depression, anxiety disorders and some personality disorders. They act by inhibiting the reuptake of serotonin into the presynaptic cell, increasing the levels of serotonin available for binding to postsynaptic receptors and/or prolonging the effects of serotonin.

The SSRIs prescribed in the UK are:

• fluoxetine (brand names Prozac, Oxactin)
• paroxetine (Seroxat)
• citalopram (Cipramil)
• escitalopram (Cipralex)
• sertraline (Lustral)
• fluvoxamine (Faverin)

1.2 Selective serotonin and noradrenaline reuptake inhibitors (SNRIs)

Dual action serotonin and noradrenaline reuptake inhibitors (SNRIs) are a class of antidepressant drug used to treat major depression and other disorders. They are a newer class of drug than selective serotonin reuptake inhibitors (SSRIs), but act in a similar way, altering neurotransmitter levels in the brain, or prolonging their effects. SNRIs act particularly on serotonin and noradrenaline.

The SNRIs prescribed in the UK are:

• venlafaxine - brand names:
  • Bonilux
  • Depefex
  • Foraven
  • Politid
  • Venlalic
  • Winfex
  • Efexor
• duloxetine - brand names
  • Cymbalta
  • Yentreve

Venlafaxine was the first SNRI to be marketed (in 1994) and is the most commonly used medicine in this class. It is used to prevent recurrence of major depressive episodes and to treat:

• major depressive disorders
• generalised anxiety disorder
• social anxiety disorder and panic disorder

For the treatment of major depressive disorder, generalised anxiety disorder and diabetic peripheral neuropathic pain, duloxetine is marketed as Cymbalta. For the treatment of stress urinary incontinence, duloxetine is marketed as Yentreve. Cymbalta and Yentreve should be prescribed for their correct intended use, and should not be used together.

2. SSRIs/SNRIs and the risk of suicidal behaviour

There is a risk of suicidal behaviour with the use of any SSRI or SNRI, particularly when used by children, adolescents or young adults.

SSRIs and SNRIs are effective medicines, and the balance of risks and benefits in adults of all medicines in these drug classes remains positive in their licensed indications. However, some cases of suicidal thoughts have been reported with SSRI and SNRI use. MHRA and Commission on Human Medicines (CHM), have investigated and monitored this safety issue since these products were first licensed.

In May 2003, an SSRI expert working group was established to consider the safety of SSRIs, including the issue of suicidal risk. The group reviewed all available data and concluded the following that:

• generally in depressed patients the risk of suicide is greatest around the time of their presentation to medical services, however the risk of suicide may increase in the early stages of treatment for depressive illness
• a modest increase in the risk of suicidal thoughts and self-harm for SSRIs compared with placebo cannot be ruled out
• there is insufficient evidence of any marked difference in suicidal risk between the different SSRIs, or between SSRIs and other antidepressants

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).

There are no marked differences in suicidal risk between the different classes and types of antidepressant and there is no evidence that the use of SSRIs or SNRIs leads to an increased risk of suicide in the general population.

On the basis of the UK and European reviews, the wording below on the risk of suicidal thoughts and behaviour with antidepressants was agreed in Europe in 2008 for inclusion in PILs and SPCs for all antidepressants, including SSRIs and SNRIs.

Thoughts of suicide and worsening of your depression or anxiety disorder

If you are depressed and/or have anxiety disorders you can sometimes have thoughts of harming or killing yourself. These may be increased when first starting antidepressants, since these medicines all take time to work, usually about two weeks but sometimes longer. You may be more likely to think like this:

• if you have previously had thoughts about killing or harming yourself
• if you are a young adult; information from clinical trials has shown an increased risk of suicidal behaviour in adults aged less than 25 years with psychiatric conditions who were treated with an antidepressant

If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital straight away. You may find it helpful to tell a relative or close friend that you are depressed or have an anxiety disorder, and ask them to read this leaflet. You might ask them to tell you if they think your depression or anxiety is getting worse, or if they are worried about changes in your behaviour.

It is important to remember that SSRIs and SNRIs are effective medicines for all their indicated conditions and that the balance of risks and benefits of all SSRIs in adults remains positive.

3. SSRIs/SNRIs and the risk of withdrawal reactions

All SSRIs and SNRIs may be associated with withdrawal reactions on stopping or reducing treatment. Symptoms of withdrawal such as anxiety, agitation and insomnia have been reported after a dose decrease or stopping treatment with SSRIs and SNRIs.

Previous safety considerations on SSRIs led to updated warnings for all SSRIs on the potential risk of withdrawal reactions after stopping treatment. Further assessment of available evidence by an expert group on the safety of SSRIs led to the following conclusions on withdrawal:

• all SSRIs and SNRIs may be associated with withdrawal reactions on stopping or reducing treatment
• paroxetine and venlafaxine seem to be associated with a greater frequency of withdrawal reactions than other SSRIs - the most commonly experienced withdrawal reactions are:
  • dizziness
  • numbness and tingling
  • gastrointestinal disturbances (particularly nausea and vomiting)
  • headache
  • sweating
  • anxiety
  • sleep disturbances
• awareness of the risk of withdrawal reactions associated with SSRIs and SNRIs needs to be increased among both prescribers and patients
• withdrawal reactions are less severe when the dose is gradually decreased or ‘tapered off’ over several weeks

Before starting SSRI treatment there should be a discussion between the prescriber and the patient about the possibility of withdrawal reactions. Such discussions should include informing women of child-bearing years that use of SSRIs while pregnant could lead to withdrawal symptoms in the new-born child.

4. Safety concerns with SSRI/SNRI use in pregnancy

SSRIs and SNRIs cross the placenta in pregnant women and have the potential to affect the unborn fetus.

4.1 Persistent pulmonary hypertension in newborn infants

Persistent pulmonary hypertension in the newborn (PPHN) is a disorder of the heart and respiratory system in a newborn baby which causes breathing and circulation difficulties and is associated with an increase in mortality.

The symptoms usually begin during the first 24 hours after birth and include:

• fast breathing
• inability to sleep or feed properly
• a blue-ish tinge to the skin
• vomiting

After a review of data from scientific studies (Chambers and colleagues, 2006; Kallen and Olausson, 2008), MHRA advised healthcare professionals that:

• SSRI use later in pregnancy, particularly after the twentieth week, may increase the risk of PPHN; the normal background risk of PPHN is 1–2 cases per 1000 pregnancies and this risk increases to approximately 5 cases per 1000 pregnancies with maternal SSRI use
• although there is currently no evidence for an association of PPHN with SNRIs, a potential risk cannot be ruled out as their mechanisms of action are very similar

The Summaries of Product Characteristics (SPC) for all SSRIs and SNRIs have been updated with the new information.

4.2 Neonatal serotonergic effects and withdrawal symptoms

Some evidence suggests that exposing an unborn child to SSRIs or SNRIs in the womb is associated with complications when the baby is born, such as neonatal abstinence syndrome (NAS) - a withdrawal syndrome seen in newborn babies. Therefore, MHRA advises that:

• discontinuation/withdrawal symptoms may occur in newborns if SSRIs or SNRIs are used until or shortly before birth
• pregnant women should only use SSRIs or SNRIs after discussing any potential risks to their unborn child with their doctor.
• female patients should inform their doctor if they become pregnant during treatment with these drugs
• newborn babies should be observed by a health professional if maternal use of an SSRI or SNRI continues into the later stages of pregnancy, particularly the third trimester

Symptoms which may occur in newborn babies after maternal SSRI/SNRI use in later stages of pregnancy include:

• irritability
• tremor
• muscle weakness
• persistent crying
• difficulty in sucking or sleeping.

These symptoms could be due to either serotonergic effects or discontinuation symptoms. In the majority of cases the complications begin immediately or soon (less than 24 hours) after delivery.

4.3 Other safety concerns with SSRI use during pregnancy

Use of SSRIs in the first 3 months of pregnancy and the risk of birth defects

It is estimated that between 7 and 20% of pregnant women may experience symptoms of depression (Marcus and colleagues, 2003, Bennett and colleagues, 2004. It is important to treat depression in pregnancy, as it is associated with a variety of adverse outcomes for both the unborn baby and the mother. It is also important that the safety of any antidepressant medicines given in pregnancy is adequately monitored.

A review of available data in 2005 assessed a possible association between exposure to paroxetine (brand name Seroxat) in the first trimester of pregnancy and the risk of congenital malformations (birth defects) in the developing fetus.

The results suggest that there is an increased risk of all malformations, particularly cardiovascular, in infants exposed to paroxetine during the first trimester of pregnancy (less than 2/100 pregnancies). The background (naturally occurring) incidence of any congenital malformation is approximately 1/100.

A similar meta-analysis on possible congenital defects with SSRI use was conducted for fluoxetine in 2009. The results of this analysis suggest that fluoxetine use in pregnancy is not associated with a risk of non-cardiac birth defects. However the results also showed that the use of fluoxetine in the first trimester of pregnancy is associated with a small increased risk (less than 2/100 pregnancies) of congenital cardiac defects in the unborn child.

The level of risk is similar to the level of risk associated with maternal paroxetine use. The background (naturally-occurring) incidence of congenital cardiac defects is approximately 1/100.

5. Other safety concerns with SSRI use

5.1 SSRI antidepressants and the risk of bone fractures

MHRA has issued advice to healthcare professionals and patients about a small increased risk of fractures associated with the use of SSRIs and another group of antidepressant medicines called tricyclic antidepressants (TCAs).

A review of epidemiological studies shows an increased risk of bone fractures in patients receiving SSRIs and TCAs.

The mechanism leading to this increased risk is unclear and is probably multifactorial. Healthcare professionals should be aware of the potential risk of fractures in patients taking, or starting to take SSRIs or TCAs, to better inform their discussions with patients and decision-making processes in prescribing these medicines.

6. The effects of SSRIs on tamoxifen effectiveness

Some SSRIs may interfere with the cancer-fighting actions of tamoxifen if they are given around the same time.

Tamoxifen is a medicine used to treat oestrogen-receptor-positive breast cancer in premenopausal and postmenopausal women. Tamoxifen is a prodrug and the formation of its active metabolite endoxifen is mediated by cytochrome P450 isoenzyme 2D6 (CYP2D6).

Some medicines such as SSRIs (which are commonly prescribed to treat depression in women with breast cancer) block the function of CYP2D6, and may therefore also interfere with the cancer-fighting actions of tamoxifen if they are given around the same time. MHRA advises that:

• the SSRIs paroxetine (brand name Seroxat) and fluoxetine (Prozac) should be avoided in patients taking tamoxifen
• the use of any medicine that is known to be a strong or potent CYP2D6 inhibitor should be avoided in patients taking tamoxifen

7. Venlafaxine and risks associated with overdose

In December 2004, concerns about the potential for cardiotoxicity and toxicity in overdose with venlafaxine (Efexor) led to its restriction to specialist initiation and contraindications in patients with heart disease.

In May 2006, MHRA concluded a review of all the latest safety evidence related to venlafaxine, particularly the risks associated with overdose. Prescribing advice for venlafaxine was updated:

• specialist supervision is needed for severely depressed or hospitalised patients who require venlafaxine doses of 300 mg daily or more
• cardiac contra-indications are more targeted towards high-risk groups
• as previously, patients with uncontrolled hypertension should not take venlafaxine, and blood pressure monitoring is recommended for all patients
• concomitant SSRI use should be restricted to specialist use
• other drug interactions are a possibility, particularly CYP3A4 inhibitors and CYP2D6 inhibitors
• these interacting drugs should only be prescribed when strictly indicated

8. SSRI/SNRI interaction with methylthioninium chloride

Methylthioninium chloride (formerly known as methylene blue) is licensed to treat a blood disorder called methaemoglobinaemia. It is also sometimes used ‘off-label’ as a visualising agent in surgical procedures or to manage uncontrollable hypotension during surgery, although these are not licensed uses.

MHRA has investigated reports of central nervous system (CNS) toxicity associated with methylthioninium use. All the cases occurred after the off-label use of methylthioninium as a visualising agent in parathyroid or thyroid surgery, or for the management of uncontrollable hypotension during cardiac surgery. In almost all of the cases, the patients were also being treated with serotonergic drugs (such as SSRIs and SNRIs).

After investigation, MHRA advised that:

• there is a possibility of CNS toxicity with methylthioninium use in patients treated with serotonergic drugs such as SSRI antidepressants, the SNRI venlafaxine, and clomipramine
• intravenous methylthioninium chloride should be avoided in patients who have been treated recently with serotonergic antidepressants, including SSRIs, clomipramine, and venlafaxine

Healthcare professionals were also advised to carefully evaluate off-label use of methylthioninium chloride before starting treatment. Information on this safety issue has been added to the product information for methylthioninium chloride.