Major classes of antidepressants include: Selective serotonin reuptake inhibitors (SSRIs) Serotonin–noradrenaline reuptake inhibitors (SNRIs) Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) This article focuses on SSRIs and SNRIs, outlining their mechanism of action, cautions, contraindications, side effects, and clinically significant interactions. Mechanism of Action Depression is linked to low levels of serotonin, noradrenaline, and dopamine in the brain. SSRIs and SNRIs inhibit presynaptic reuptake of neurotransmitters → greater neurotransmitter availability at the postsynaptic neuron → enhanced neurotransmission in mood-regulating pathways. Class Primary Action Secondary Effects Examples Indications SSRIs Inhibit presynaptic reuptake of serotonin via the serotonin transporter (SERT) ↑ Serotonin in synaptic cleft → improved mood Fluoxetine, Sertraline, Citalopram, Escitalopram, Paroxetine First-line for depression and anxiety disorders SNRIs Inhibit reuptake of both serotonin (SERT) and noradrenaline (NET) Some (venlafaxine, duloxetine) weakly inhibit dopamine reuptake ↑ Serotonin, noradrenaline +/- dopamine in synaptic cleft → improved mood Venlafaxine, Duloxetine Depression and anxiety disorders Also used for diabetic neuropathy and stress urinary incontinence (duloxetine) Created in BioRender. Boucher, M. (2025) https://BioRender.com/wuqvbty Fig 1: Mechanism of action of SSRIs and SNRIs Cautions and Contraindications Cautions Contraindications SSRIs and SNRIs are ulcerogenic – should be prescribed cautiously with other drugs that are ulcerogenic/in history of GI bleeding Diabetes (can affect diabetic control) Epilepsy (can cause convulsions & reduce seizure threshold) Susceptibility to angle-closure glaucoma Renal impairment (citalopram and escitalopram) Delay in onset of effect Poorly controlled epilepsy Citalopram and escitalopram – known QT prolongation / concurrent use of drugs known to prolong QT Severe hepatic impairment (sertraline) Use with monoamine oxidase inhibitors (MAOI) – risk of serotonin syndrome or neuroleptic malignant syndrome Hepatic impairment and CrCl <30ml/min (duloxetine) 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. Reported and potential side effects include the following: System Adverse Effects Cardiovascular QT prolongation (citalopram, escitalopram, venlafaxine); ↑ BP & HR (SNRIs) Gastrointestinal Nausea, diarrhoea, GI bleeding CNS Insomnia, agitation, dizziness, headache Endocrine Hyponatraemia (SIADH, especially in elderly) Sexual Reduced libido, sexual dysfunction (may persist post-treatment) Musculoskeletal Increased risk of bone fractures (SSRIs) Hepatic Hepatic impairment due to extensive liver metabolism (sertraline) Other Dry mouth, sweating, withdrawal symptoms Interactions General interactions Serotonin syndrome with MAOIs, lithium, tramadol and TCAs. QT prolongation with other drugs that prolong QT interval: lithium, venlafaxine, 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) Grapefruit juice increases levels of sertraline, not recommended to use together 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 (moderate inhibitor of CYP2D6), caution with drugs metabolised by CYP2D6 such as tricyclic antidepressants. Withdrawal syndrome 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: Drug Half-life Withdrawal Risk Fluoxetine 4–6 days Low Sertraline 26 hours Moderate Paroxetine 24 hours High Citalopram 36 hours Moderate Escitalopram 30 hours Moderate Venlafaxine 5 ±2 h (metabolite: 11 ±2 h) High Duloxetine 12 hours Moderate Withdrawal symptoms include: Dizziness Sleep disturbance Agitation or anxiety Nausea and/or vomiting Tremor Headache References Onset of action of antidepressants | The BMJ Antidepressant drugs | Treatment summaries | BNF | NICE SSRIs | Prescribing information | Depression | CKS | NICE Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs): use and safety – GOV.UK (www.gov.uk) Venlafaxine 75 mg prolonged-release capsules, hard – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) Duloxetine 30mg GR Capsules, hard – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) Do you think you’re ready? Take the quiz below Pro Feature - Quiz SSRIs and SNRIs Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article