High dose SSRIs for the treatment of depression

• 20mg: citalopram/fluoxetine/paroxetine
• 10mg: escitalopram
• 50mg: sertraline

Standard SSRI doses provide the optimal balance between efficacy and minimising adverse effects and harms. This is due to their flat dose response curve for the treatment of depression, meaning that ‘20’s plenty and 50’s enough’ to provide the full antidepressant effect. (Standard doses provide optimal serotonin transporter occupancy.)¹²⁰ Previously prescribers have been heavily criticised for prescribing subtherapeutic licensed doses of TCAs for the treatment of depression. (Licensed dose is the approved dose or dose range that medicines are licensed to be prescribed at by the regulatory authority – Medicines and Healthcare products Regulatory Agency (MHRA) – for the condition that they approved to treat, e.g. sertraline for depression treatment has a dose range of 50mg to 200mg per day.^121,122  While TCAs and SNRIs demonstrate dose response effects, with larger doses being more effective for depression treatment,^39,40,53 higher than standard daily doses of SSRIs (20mg citalopram/fluoxetine/paroxetine, 50mg sertraline or 10mg escitalopram) do not provide better response rates, not even for poor or partial responders.^39-42,44

While a range of campaigns and guidelines for depression have heavily promoted the message ‘to increase the dose’ of antidepressants for poor and non-responders,^36,123-125 a minority of guidelines have highlighted the differences in response and efficacy between SSRIs and other antidepressants.20,126 Individuals and prescribers may have expectations that higher doses are more effective for routine treatment of depression,^5,11 in part this may be due to guidelines or training, as well as individual or societal expectations and beliefs regarding medicines.^29,127,128 For a small minority of individuals, where a trial of higher dose SSRI is considered appropriate, follow up review within two to four weeks should be arranged to assess response to treatment and address any adverse effects. It is known that early improvement predicts a stable response.^73,129 For anxiety disorders SSRI dose response effects are mixed. GAD guidelines indicate no clear indication of a dose response relationship, whereas obsessive compulsive disorder guidelines indicate that higher SSRI doses can be more efficacious.^37,69,89

In 2011, in the UK, the MHRA issued advice regarding new maximum daily dose restrictions, contraindications, and warnings for citalopram and escitalopram use.⁹⁸ Health boards issued local advice on reviewing citalopram/escitalopram doses: reviewing, reducing doses and if necessary switching to an alternative antidepressant where appropriate.¹³⁰ Anecdotally from prescribers and general practice feedback, of those individuals that were reviewed: some stopped, some required a switch to an alternative antidepressant; while the vast majority that were required to continue treatment were continued on lower doses, as per MHRA advice, without worsening of their depressive symptoms.