PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
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.
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. Some pharmacological trial data also cast doubt on the efficacy of SSRIs compared with placebo. Despite this, manipulation of the serotonin axis by SSRIs seems to be beneficial in treating patients with moderate-to-severe depression.
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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. However, it may be that SJW is safe and effective in the short-term relief of depression. SJW may be more useful in milder depression. Further randomised controlled trials, of longer duration, are necessary for SJW in depression.
Currently available Selective serotonin reuptake inhibitors
Refer to each individual drug's Specific Product Characteristics (SPC) for details.
- Depression - all SSRIs are licensed for this indication; paroxetine is licensed only for the treatment of major depression.
- Panic disorder - citalopram, escitalopram, paroxetine.
- Social anxiety disorder/social phobia - escitalopram, paroxetine.
- Bulimia nervosa - fluoxetine.
- Obsessive-compulsive disorder - fluoxetine, fluvoxamine, paroxetine, sertraline (the latter under specialist supervision in children).
- Post-traumatic stress disorder - paroxetine, sertraline (latter in females only).
- Generalised anxiety disorder - paroxetine.
- Premenstrual disorder (unlicensed).
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 recent meta-analysis failed to find any difference with SSRIs.
Use in children and adolescents
A meta-analysis of a number of trials of SSRIs in children suggests that the benefits of SSRIs appear to outweigh any suicidal risks in a number of conditions including depression and anxiety disorders. Furthermore, the use of SSRIs in children is associated with a number of problems of which increased activity is prominent.
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, gastrointestinal (GI) bleeding, or history of GI bleeding.
- Hepatic/renal impairment.
- Pregnancy and breast-feeding - seek specialist advice, eg National Teratology Information Service (neonatal withdrawal syndrome, particularly with paroxetine).
- Young adults (possible increased suicide risk).
- Suicidal ideation.
- With monoamine oxidase inhibitors (MAOIs)/moclobemide: serious toxicity risk. If changing from an SSRI, an MAOI or moclobemide should not be started until: 5 weeks after stopping fluoxetine; 2 weeks after stopping sertraline; 1 week after other SSRIs. Also, more than 5 weeks should elapse if on high doses or chronic use of fluoxetine. If changing from an MAOI, do not start SSRIs until 2 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.
- GI side-effects such as nausea, vomiting, dyspepsia and constipation are quite common. Anorexia or increased appetite with weight gain may occur.
- Hypersensitivity reactions with rash may be encountered and discontinuation should be considered as it may herald a vasculitis.
- Urticaria, angioedema, 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 to consider the diagnosis in all elderly patients on antidepressants who develop drowsiness, confusion or convulsions.
- 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.
- Serotonin syndrome - this can occur with overdose or concurrent MAOI use. It includes altered mental state, autonomic dysfunction, and neuromuscular abnormalities.
- 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 fifty on SSRIs.
Initiation and discontinuation
- 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 get help if agitation/suicidal feelings occur.
- Patients should be reviewed 1-2 weeks after starting treatment.
- A trial of at least 4-8 weeks (6 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.
These may occur after stopping SSRIs. GI symptoms, 'chills', insomnia, hypomania, anxiety and restlessness may occur. Aim to reduce the dose gradually over about 4 weeks or so to try to avoid/ameliorate this. In patients who have taken the drug long-term, they may need 6 months or so to withdraw gradually.
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 & references
- Depression in children and young people; NICE (September 2005)
- Badawy M et al; Toxicity, Selective Serotonin Reuptake Inhibitor, eMedicine, Apr 2010
- 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 15;58(6):451-6. Epub 2005 Jul 14.
- Taylor S, Stein MB; The future of selective serotonin reuptake inhibitors (SSRIs) in psychiatric treatment. Med Hypotheses. 2006;66(1):14-21. Epub 2005 Oct 5.
- Kirsch I, Deacon BJ, Huedo-Medina TB, et al; Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008 Feb;5(2):e45.
- Turner EH, Rosenthal R; Efficacy of antidepressants. BMJ. 2008 Mar 8;336(7643):516-7. Epub 2008 Mar 4.
- Arroll B, Macgillivray S, Ogston S, et al; Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med. 2005 Sep-Oct;3(5):449-56.
- Geddes JR, Freemantle N, Mason J, et al; SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev. 2000;(2):CD001851.
- Antidepressant Drug Adherence, Bandolier; Evidence based thinking about health care
- 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 BMJ. 2005 Mar 5;330(7490):503. Epub 2005 Feb 11.
- Williams JW Jr, Holsinger T; St John's for depression, worts and all. BMJ. 2005 May 14;330(7500):E350
- Specific Product Characteristics (SPC) Citalopram®; Lundbeck Limited; Feb 2008
- Specific Product Characteristics (SPC) Fluoxetine®; Discovery Pharmaceuticals Ltd; Nov 2010
- Specific Product Characteristics (SPC) Fluvoxamine®; Solvay Healthcare Ltd; Sept 2010
- Specific Product Characteristics (SPC) Paroxetine®; GlaxoSmithKline UK; July 2010
- Specific Product Characteristics (SPC) Sertraline®; Wockhardt UK Ltd; June 2009
- No authors listed; Selective serotonin reuptake inhibitors in obsessive-compulsive disorder. Drug Ther Bull. 1995 Jun;33(6):47-8.
- No authors listed; SSRIs for premenstrual dysphoric disorder. Drug Ther Bull. 2002 Sep;40(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 May;111(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 Apr;68(4):604-10.
- Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors, Medicines and Healthcare products Regulatory Agency (MHRA)
- Bridge JA, Iyengar S, Salary CB, et al; Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007 Apr 18;297(15):1683-96.
- Zuckerman ML, Vaughan BL, Whitney J, et al; Tolerability of selective serotonin reuptake inhibitors in thirty-nine children under age seven: a retrospective chart review. J Child Adolesc Psychopharmacol. 2007 Apr;17(2):165-74.
- Taylor D et al; The Maudsley Prescribing Guidelines 2005-2006
- No authors listed; Do SSRIs cause gastrointestinal bleeding? Drug Ther Bull. 2004 Mar;42(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 28;168(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 5-11;365(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 19;330(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 Jun;120(6):525-30. Epub 2007 Apr 30.
- Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al; SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997 Fall;23(3):176-94.
- Fergusson D et al; Systematic review of SSRI related suicide
- Evans CE, Sebastian J; Serotonin syndrome. Emerg Med J. 2007 Apr;24(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 21;6:7.
- Richards JB, Papaioannou A, Adachi JD, et al; Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007 Jan 22;167(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 May;10(2):46.
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Dr Gurvinder Rull
Dr Gurvinder Rull