SSRIs and SNRIs

Mechanism of Action

Depression is linked to low levels of serotonin (5-hydroxytrypamine), noradrenaline, and dopamine in the brain.

SSRIs and SNRIs inhibit presynaptic reuptake of neurotransmitters leading to greater neurotransmitter availability at the postsynaptic neuron and thus enhanced neurotransmission in mood-regulating pathways. Vortioxetine is a newer SSRI which also demonstrates partial agonist activity at 5HT-1a and 5HT-1b receptors and is an antagonist at other 5HT receptors such as 3a. Sertraline is also a weak inhibitor of dopamine reuptake.

Created in BioRender. Boucher, M. (2025) https://BioRender.com/wuqvbty

Fig 1: Mechanism of action of SSRIs and SNRIs

Cautions

SSRIs and SNRIs are associated with an increased risk of gastrointestinal irritation and bleeding. They are considered ulcerogenic and should therefore be prescribed cautiously in patients with a history of peptic ulcer disease or gastrointestinal bleeding, and when used concomitantly with other ulcerogenic or bleeding-risk medications (e.g. NSAIDs, antiplatelets, or anticoagulants).

Caution is also required in patients with diabetes, as antidepressant therapy can affect glycaemic control and may necessitate closer monitoring of blood glucose levels. In individuals with epilepsy, SSRIs and SNRIs can lower the seizure threshold and increase the risk of convulsions, so careful assessment and monitoring are advised.

Patients with susceptibility to angle-closure glaucoma should be monitored, as these agents may precipitate an acute episode. Renal impairment requires particular attention with certain drugs, notably citalopram and escitalopram, where dose adjustment or closer monitoring may be necessary.

Finally, clinicians and patients should be aware that SSRIs and SNRIs have a delayed onset of therapeutic effect. Symptomatic improvement may take several weeks, and patients should be counselled accordingly to encourage adherence and manage expectations.

Contraindications

SSRIs and SNRIs are contraindicated in patients with poorly controlled epilepsy due to the increased risk of seizure activity.

Citalopram and escitalopram are associated with QT interval prolongation and are contraindicated in patients with known QT prolongation or in those taking other medications that prolong the QT interval. Venlafaxine can also cause QT prolongation but it’s use is only cautioned in this condition.

Severe hepatic impairment is a contraindication for certain agents, such as sertraline, due to extensive hepatic metabolism. Duloxetine is contraindicated in patients with hepatic impairment and in those with severe renal impairment (creatinine clearance <30 mL/min).

Concomitant use with monoamine oxidase inhibitors (MAOIs) is contraindicated because of the risk of life-threatening serotonin syndrome or neuroleptic malignant syndrome. Appropriate washout periods must always be observed when switching between these drug classes.

Adverse Effects

SSRIs are the first line antidepressant in the UK, and are widely used. SSRIs and SNRIs have overlapping mechanisms of action so also have similar reported side effects. SSRIs are less sedating and have fewer antimuscarinic effects compared to TCAs. Reported and potential side effects include the following:

Interactions

General Interactions

• Serotonin syndrome with MAOIs, lithium, tramadol and TCAs.
• QT prolongation with other drugs that prolong QT interval: lithium, amiodarone, haloperidol, TCAs 
• Hyponatraemia with other drugs that also cause hyponatraemia: diuretics, NSAIDs, antipsychotics, carbamazepine, CCBs, ACE-inhibitors, laxatives 
• Caution with medications that increase bleeding risk: antiplatelets, NSAIDs, anticoagulants

CYP-mediated Interactions

• Caution with venlafaxine and CYP3A4 inhibitors (metabolised primarily via CYP2D6, also to a less active metabolite by CYP3A4).
• Reduced tamoxifen levels (a prodrug mediated by CYP2D6) with fluoxetine and paroxetine which inhibit enzyme CYP2D6
• Duloxetine (metabolised by CYP1A2) 
  • Not recommended with fluvoxamine (potent inhibitor of CYP1A2) → ↑ exposure to  duloxetine 
  • Smoking induces CYP1A2; smokers have been found to have almost 50% lower plasma concentrations of duloxetine compared with non-smokers. 
• Duloxetine, paroxetine and fluoxetine (moderate inhibitor of CYP2D6), caution with drugs metabolised by CYP2D6 such as tricyclic antidepressants due to risk of TCA toxicity. 
• Grapefruit juice increases levels of sertraline, not recommended to use together (CYP3A4 mediated)

Withdrawal Syndrome

In the event of stopping therapy, doses should be gradually reduced over at least 1-2 weeks to reduce risk of withdrawal effects. Withdrawal symptoms usually occur within the first few days of discontinuing treatment and resolve within 2 weeks (but effect can be prolonged for 2-3 months or more).

Paroxetine and venlafaxine seem to be associated with a greater frequency of withdrawal reactions than other SSRIs. Fluoxetine is less likely to precipitate withdrawal syndrome as it possesses a long half life. 

Approximate half lives of SSRIs & SNRIs: 

Withdrawal symptoms include:

• Dizziness
• Sleep disturbance 
• Agitation or anxiety
• Nausea and/or vomiting 
• Tremor
• Headache 

References

1. Onset of action of antidepressants | The BMJ
2. Antidepressant drugs | Treatment summaries | BNF | NICE
3. SSRIs | Prescribing information | Depression | CKS | NICE
4. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs): use and safety – GOV.UK (www.gov.uk)
5. Venlafaxine 75 mg prolonged-release capsules, hard – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
6. Duloxetine 30mg GR Capsules, hard – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
7. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.