Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) in central nervous system (CNS) synapses, thus increasing the intra-synaptic concentration of serotonin.
In recent years, there has been increasing awareness of the sometimes severe withdrawal symptoms experienced by some patients. This has led to a re-evaluation of the relative risks and benefit profile of SSRIs.
Depression and serotonin
It has long been postulated that a deficiency in CNS serotonergic activity is the cause of, or a predisposing factor for, depression. However, the evidence for this association is largely circumstantial and it certainly does not represent an adequate and full model for depression, probably due to there being multiple aetiological factors.
Current guidance on use of SSRIs
National Institute for Health and Care Excellence guidance recommends SSRI use in adults with:
- Mild-to-moderate depression where low-intensity psychosocial intervention has not helped.
- Patients with fewer than five of the symptoms required to make a diagnosis of depression (termed subthreshold depression).
- Moderate-to-severe depression with concomitant high-intensity psychosocial interventions.
The Royal College Of Psychiatrists 2019 position statement on antidepressants and depressionadvises that:
- In moderate-severe depression, evidence-based psychological treatments should be used first-line, and antidepressants considered if:
- The patient does not engage with treatment.
- The patient does not respond to treatment.
- The patient has more severe symptoms.
- Antidepressant treatment in children and adolescents should be confined to second-line treatment for moderate-to-severe depression except in exceptional circumstances. See the separate Depression in Children and Adolescents article for more details.
- Antidepressants are not generally recommended for mild and subthreshold depression but may be considered if the patient has a history of moderate or severe depression, or if symptoms have been present for at least two years or do not respond to other interventions.
- Full information must be shared about potential level of benefits and harms, including withdrawal, and concordance about initiation and continuation.
- Discontinuation should involve tapering or slow reduction - see section on withdrawal below.
Selective serotonin reuptake inhibitors versus other antidepressants
SSRIs appear to be similar in efficacy to the older tricyclic antidepressants (TCAs) but have fewer antimuscarinic side-effects and are less cardiotoxic in overdosage. Although SSRIs are, on the whole, better tolerated than older antidepressants, the difference is not significant enough to justify always choosing SSRIs as first-line agents to treat depression.
A meta-analysis of primary care trials of SSRIs and TCAs demonstrates similar efficacy and tolerability for both, which is superior to placebo. A Cochrane review has similar findings and concludes that there are no clinically significant differences in effectiveness between SSRIs and TCAs and that treatment decisions should be based on considerations of relative patient acceptability, toxicity and cost. An analysis of antidepressant drug adherence shows that any differences in tolerability between SSRIs and TCAs are relatively subtle and difficult to extrapolate into improved acceptance of SSRIs by real patients in the real world. Where there is a significant risk of overdose, medical comorbidity which precludes antimuscarinic activity, or diabetes, SSRIs are usually preferred as first-line agents over TCAs.
St John's wort (SJW) has also been compared to SSRIs. Szegedi and colleagues reported that SJW use was associated with greater depressive symptom reduction and fewer adverse effects compared with SSRIs (paroxetine). However, a meta-analysis of SJW failed to find a substantial benefit over other forms of therapies. It may be that SJW is safe and effective in the short-term relief of depression. SJW may be more useful in milder depression[8, 9]. NICE guidance does not recommend its use, given the uncertainties in efficacy and the potential adverse effects and drug interactions with other medications.
Currently available selective serotonin reuptake inhibitors
- Fluoxetine (long half-life)
- Depression - all SSRIs are licensed for this indication; paroxetine is licensed only for the treatment of major depression.
- Panic disorder - citalopram, escitalopram, paroxetine, sertraline.
- Social anxiety disorder/social phobia - escitalopram, paroxetine.
- Bulimia nervosa - fluoxetine.
- Obsessive-compulsive disorder - fluoxetine, escitalopram, fluvoxamine, paroxetine, sertraline (the latter under specialist supervision in children) .
- Post-traumatic stress disorder - paroxetine, sertraline (the latter in females only).
- Generalised anxiety disorder - paroxetine, escitalopram.
- Premenstrual syndrome (unlicensed)[11, 12].
There have been a number of trials assessing the role of SSRIs as add-on therapy to improve the negative symptoms of schizophrenia. Unfortunately, a meta-analysis failed to find any difference with SSRIs.
Use in children and adolescents
- Antidepressants should not be prescribed except after assessment and diagnosis by a child and adolescent psychiatrist.
- Antidepressants should not be offered to children or young people except carefully selected patients under carefully monitored conditions .
- If an antidepressant is prescribed to a child or young person, it should be fluoxetine.
- Young people and their parents or carers should be informed about the rationale, the delay in onset of effect, the time course of treatment, and the possible side-effects including the appearance of suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment.
- Citalopram, escitalopram, paroxetine and sertraline show an unfavourable risk:benefit balance in the treatment of depressive illness in individuals aged <18 years.
- Citalopram and sertraline should only be considered by specialists if the young person has severe symptoms which have failed to respond to other interventions.
- Paroxetine and venlafaxine (or tricyclic antidepressants) should not be used for the treatment of depression in children and young people.
SSRIs should be discontinued or avoided in patients displaying active manic symptoms.
- History of mania.
- Epilepsy - there is the need to weigh up the risks and benefits; avoid if poorly controlled and discontinue if there is deterioration; seek specialist advice if necessary.
- Fluoxetine is reported to prolong seizure duration with concurrent electroconvulsive therapy (ECT).
- Cardiac disease - however, SSRIs (such as sertraline) are probably the safest antidepressants in cardiac disease.
- Acute angle-closure glaucoma.
- Diabetes mellitus (monitor glycaemic control after initiation).
- Concomitant use with drugs that cause bleeding or gastrointestinal (GI) bleeding, or where there is history of GI bleeding[3, 16, 17].
- Hepatic/renal impairment.
- Pregnancy and breastfeeding: seek specialist advice - eg, the National Teratology Information Service(neonatal withdrawal syndrome, particularly with paroxetine)[19, 20].
- Young adults (possible increased suicide risk).
- Suicidal ideation.
- Fluoxetine, fluvoxamine and paroxetine have a higher propensity for drug interactions than other SSRIs - consider citalopram or sertraline in people who also have chronic physical health problems
- With monoamine-oxidase inhibitors (MAOIs)/moclobemide: serious toxicity risk. If changing from an SSRI, an MAOI or moclobemide should not be started until: five weeks after stopping fluoxetine; two weeks after stopping sertraline; one week after other SSRIs. Also, more than five weeks should elapse if on high doses or there is chronic use of fluoxetine. If changing from an MAOI, do not start SSRIs until two weeks after stopping an MAOI (but after stopping moclobemide, SSRIs can be started the following day, as moclobemide has a short duration of action).
- There is a range of interactions with a number of drugs, particularly with psychiatric medications, including other antidepressants (including St John's wort (SJW)).
- The risk of serotonin syndrome is increased by interactions with other drugs and care should be taken to monitor for its symptoms when starting new therapies in those on SSRIs. It is worth checking for known interactions of the individual SSRI with other drugs when starting new treatments.
- SSRIs inhibit platelet function and thus interact with other antiplatelet agents - eg, aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitors. This interaction appears to be beneficial in acute coronary syndromes but the risk of bleeding is increased.
- Minor sedation and antimuscarinic side-effects may occur but are usually less frequent and troublesome than with TCAs.
- Compared to standard SSRIs, TCAs and venlafaxine have a higher risk of death from overdose.
- GI side-effects such as nausea, vomiting, dyspepsia and constipation are quite common. Anorexia or increased appetite with weight gain may occur.
- SSRIs are associated with an increased risk of bleeding. Consider prescribing a gastroprotective drug in older people who are taking NSAIDs or aspirin or using an alternative to an SSRI.
- Hypersensitivity reactions with rash may be encountered and discontinuation should be considered, as it may herald a vasculitis.
- Urticaria, angio-oedema, anaphylaxis, arthralgia, myalgia and photosensitivity may occur as idiosyncratic reactions. A range of minor CNS symptoms such as headache, insomnia, tremor and dizziness may occur.
- Hallucinations, drowsiness and convulsions have been reported (see the note on epilepsy under 'Cautions', above). Sexual dysfunction, including ejaculatory delay and anorgasmia may occur .
- Hyponatraemia may occur in the elderly with SSRIs and, less commonly, with other antidepressants. It is thought to be due to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. CSM advises considering the diagnosis in all elderly patients on antidepressants who develop drowsiness, confusion or convulsions[3, 24].
- Other side-effects include sweating, galactorrhoea, urinary retention, movement disorders and dyskinesias and cutaneous bleeding (purpura and ecchymoses).
- Increased risk of suicidal ideation is postulated but as yet unproven in adults[21, 25].
- Serotonin syndrome - this can occur with overdose or concurrent MAOI use. It includes altered mental state, autonomic dysfunction, and neuromuscular abnormalities[3, 26].
- There may also be an increased tendency of apathy in elderly individuals treated with SSRIs, despite improvement of depression. Similarly, some data suggest an increase in fracture risk in patients over the age of 50 years on SSRIs.
Initiation of SSRIs
- Before starting SSRIs ensure that patients are aware that they may take a few weeks to work, that they must stop if they develop a rash and that they must obtain help if agitation/suicidal feelings occur.
- Patients should be reviewed 1-2 weeks after starting treatment.
- A trial of at least 4-8 weeks (six weeks in older patients) should be given before deciding to discontinue/change an agent.
- If there is partial response, allow another two weeks to decide if effective or not.
- There is little evidence to support the use of dose escalation in patients who do not respond to standard doses.
- After remission of symptoms, continue for at least 4-6 months (12 months in the older patient).
- Maintenance treatment may be needed in those with recurrent depression.
Withdrawal of SSRIs
- Advise patients to discuss with their doctor before stopping.
- Advise patients that abrupt discontinuation, or missed or partial doses, can result in discontinuation symptoms including:
- Problems sleeping.
- Abdominal symptoms.
- Altered sensations (for example, electric shock sensations in the head).
- Altered feelings (for example, irritability, anxiety or confusion).
- Explain that there is substantial variation in the severity and duration of withdrawal symptoms. These can vary from mild and self-limiting to severe symptoms which last many months.
- Reduce the dose gradually, normally over a four-week period, but consider a much slower withdrawal, especially for drugs such as paroxetine (which has a shorter half-life).
- If discontinuation symptoms occur:
- Monitor and reassure if symptoms are mild.
- Consider re-introducing the original antidepressant or another with a longer half-life, and reduce gradually while monitoring symptoms.
As there is a potential risk of increased suicidal ideation in those taking SSRIs, it is a good idea to ask explicitly about these symptoms and to document them before initiating these agents, and when reviewing a patient on SSRIs.
Further reading and references
Maes M and Meltzer H; The Serotonin Hypothesis of Major Depression (2000). Website of American College of Neuropsychopharmacology
Willis-Owen SA, Turri MG, Munafo MR, et al; The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry. 2005 Sep 1558(6):451-6. Epub 2005 Jul 14.
Depression in adults: recognition and management; NICE Clinical Guideline (April 2018)
Arroll B, Elley CR, Fishman T, et al; Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009 Jul 8(3):CD007954. doi: 10.1002/14651858.CD007954.
Antidepressant Drug Adherence; Bandolier
Szegedi A, Kohnen R, Dienel A, et al; Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ. 2005 Mar 5330(7490):503. Epub 2005 Feb 11.
Williams JW Jr, Holsinger T; St John's for depression, worts and all. BMJ. 2005 May 14330(7500):E350
Cui YH, Zheng Y; A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatr Dis Treat. 2016 Jul 1112:1715-23. doi: 10.2147/NDT.S106752. eCollection 2016.
British National Formulary (BNF); NICE Evidence Services (UK access only)
No authors listed; SSRIs for premenstrual dysphoric disorder. Drug Ther Bull. 2002 Sep40(9):70-2.
Shah NR, Jones JB, Aperi J, et al; Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder: a meta-analysis. Obstet Gynecol. 2008 May111(5):1175-82.
Sepehry AA, Potvin S, Elie R, et al; Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. J Clin Psychiatry. 2007 Apr68(4):604-10.
Depression in children and young people: identification and management; NICE Guidance (June 2019)
The Maudsley Prescribing Guidelines
No authors listed; Do SSRIs cause gastrointestinal bleeding? Drug Ther Bull. 2004 Mar42(3):17-8.
Schalekamp T, Klungel OH, Souverein PC, et al; Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med. 2008 Jan 28168(2):180-5.
UK Teratology Information Service; Regional Drug and Therapeutics Centre (RDTC)
Sanz EJ, De-las-Cuevas C, Kiuru A, et al; Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet. 2005 Feb 5-11365(9458):482-7.
Walling A; SSRI Use for Treatment of Depression During Pregnancy. Am Fam Phys 2005 Nov 1
Gunnell D, Saperia J, Ashby D; Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review. BMJ. 2005 Feb 19330(7488):385.
Ziegelstein RC, Meuchel J, Kim TJ, et al; Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med. 2007 Jun120(6):525-30. Epub 2007 Apr 30.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs): use and safety; Medicines and Healthcare products Regulation Authority (MHRA), December 2014
Fergusson D, Doucette S, Glass KC, et al; Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ. 2005 Feb 19330(7488):396.
Evans CE, Sebastian J; Serotonin syndrome. Emerg Med J. 2007 Apr24(4):e20.
Wongpakaran N, van Reekum R, Wongpakaran T, et al; Selective serotonin reuptake inhibitor use associates with apathy among depressed elderly: a case-control study. Ann Gen Psychiatry. 2007 Feb 216:7.
Richards JB, Papaioannou A, Adachi JD, et al; Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007 Jan 22167(2):188-94.
Heres S, Kissling W, Leucht S; Review: little evidence to support dose escalation of selective serotonin reuptake inhibitors in non-responders. Evid Based Ment Health. 2007 May10(2):46.