Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) in CNS synapses, thus increasing the intra-synaptic concentration of serotonin.

It has long been postulated that a deficiency in CNS serotonergic activity is the cause of, or a predisposing factor for, depression.¹ 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.² Some pharmacological trial data also cast doubt on the efficacy of SSRIs compared to placebo.^3,4,5 Despite this, manipulation of the serotonin axis by SSRIs seems to be beneficial in treating patients with moderate to severe depression.

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 recent meta-analysis of primary care trials of SSRIs and TCAs demonstrates similar efficacy and tolerability for both, that is superior to placebo.⁶ 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.⁷ 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.⁸ Where there is a significant risk of overdose, medical co-morbidity which precludes antimuscarinic activity, or diabetes, SSRIs are usually preferred as first-line agents over TCAs.

St Johns Wort (SJW) has also been compared to SSRIs. Szegedi and colleagues reported that SJW use was associated with greater depressive symptom reduction and less adverse effects compared with SSRIs (paroxetine).⁹ However a meta-analysis of SJW failed to find a substantial benefit over other forms of therapies.¹⁰ Although, it may be that SJW is safe and effective in the short-term relief of depression. SJW may be more useful in milder depression.¹⁰ Further randomised controlled trials of longer duration are necessary of SJW in depression.

• Citalopram¹¹
• Escitalopram (levorotatory isomer of citalopram)¹²
• Fluoxetine (long half-life)¹³
• Fluvoxamine¹⁴
• Paroxetine¹⁵
• Sertraline¹⁶

Refer to individual drugs 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 (latter under specialist supervision in children)¹⁷
• Post Traumatic Stress Disorder – Paroxetine, sertraline (latter in females only)
• Generalised Anxiety Disorder – Paroxetine
• Pre-menstrual disorder (unlicensed)^18,19

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.²⁰

Use in children and adolescents

Mania

SSRIs should be discontinued or avoided in patients displaying active manic symptoms.

• History of mania.
• Epilepsy - need to weigh up risks and benefits; avoid if poorly controlled and discontinue if deterioration; seek specialist advice if necessary.
• Fluoxetine reported to prolong seizure duration with concurrent ECT.
• Cardiac disease - however SSRIs (such as sertraline)are probably the safest antidepressants in cardiac disease.²⁴
• Acute angle-closure glaucoma.
• Diabetes mellitus (monitor glycaemic control after initiation).
• Concomitant use with drugs that cause bleeding, GI bleeding, or history of GI bleeding.^25,26
• Hepatic/renal impairment.
• Pregnancy and breast-feeding - seek specialist advice e.g. National Teratology Information Service²⁷ (neonatal withdrawal syndrome, particularly with paroxetine).^28,29
• Young adults (possible increased suicide risk).³⁰
• Suicidal ideation.³⁰

• With MAOIs/ moclobemide: serious toxicity risk. If changing from 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 MAOI (but after stopping moclobemide, SSRIs can be started the following day, as moclobemide has a short duration of action).
• There are a range of interactions with a number of drugs, particularly with psychiatric medications, including other antidepressants (including St. John's Wort).
• 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 e.g. aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitors. This interaction appears to be beneficial in acute coronary syndromes but the risk of bleeding is increased.³¹

• Minor sedation and antimuscarinic side effects may occur but are usually less frequent and troublesome than with TCAs.
• Gastrointestinal 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 note on epilepsy in cautions section). Sexual dysfunction including ejaculatory delay and anorgasmia may occur.³²
• 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 ADH secretion. CSM advises consider diagnosis in all elderly patients on antidepressants who develop drowsiness, confusion or convulsions.²¹
• 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.^30,33
• Serotonin syndrome - can occur with overdose or concurrent MAOI use. It includes altered mental state, autonomic dysfunction, and neuromuscular abnormalities.³⁴
• There may also be an increased tendency of apathy in elderly individuals treated with SSRIs, despite improvement of depression.³⁵ Similarly some data suggest an increase in fracture risk in patients over the age of fifty on SSRIs.³⁶

• Before starting SSRIs ensure patients are aware that they may take a few weeks to work, they must stop if they develop a rash and get help if agitation/suicidal feelings.
• 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 agent.
• If 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.³⁷
• After remission of symptoms continue for at least 4–6 months (12 months in older patient).
• Maintenance treatment may be needed in those with recurrent depression.

'Withdrawal' symptoms

These may occur after stopping SSRIs. Gastrointestinal symptoms, 'chills', insomnia, hypomania, anxiety and restlessness may occur. Aim to gradually reduce the dose over about 4 weeks or so to try and avoid/ameliorate this. In patients who have taken the drug long term may need 6 months or so to gradually withdraw.

As there is a potential risk of increased suicidal ideation in those taking SSRIs, it is a good idea to explicitly ask about and document these symptoms before initiating these agents, and when reviewing a patient on SSRIs.