Editorials Which first-line antidepressant? Choice of first-line antidepressants for since patent expiry, generic escitalopram norepinephrine, and so acts like an SNRI. A depression has been debated in psychiatric costs have fallen to match other selective 2017 Cochrane review found no advantage journals over the last 9 months, in relation serotonin reuptake inhibitors (SSRIs).4 when it was compared with SNRIs, being to the widely reported meta-analysis by less effective than duloxetine, although it Cipriani et al in the Lancet, comparing 21 ESCITALOPRAM had less severe adverse effects.9 The review antidepressants for efficacy and tolerability.1 So why not choose escitalopram first- criticised a relative lack of direct head-to- They found that agomelatine, amitriptyline, line? One reason is safety concerns. As head comparisons between vortioxetine and escitalopram, mirtazapine, paroxetine, with citalopram, it can cause significant the SSRIs, and the reliance placed on the venlafaxine, and vortioxetine were more QTc prolongation, potentially increasing results of NMAs to define its role.9 Given that effective than other antidepressants.1 the risk of ventricular arrhythmias, which a year’s treatment costs £360,4 vortioxetine They also found agomelatine, citalopram, led to the 2011 Medicines and Healthcare also should remain a third-line choice. escitalopram, fluoxetine, sertraline, and products Regulatory Agency warning, vortioxetine to be relatively better tolerated restricting use and doses,5 following which MIRTAZAPINE than others.1 Three antidepressants with citalopram and escitalopram prescribing What about mirtazapine, which Cipriani et higher efficacy also had relatively high both fell.3 QTc prolongation is less of an al found to be ranked highly for efficacy, but acceptability: agomelatine, escitalopram, issue with sertraline and fluoxetine. Also, not so highly for acceptability? It is relatively and vortioxetine. So should these some escitalopram comparison studies use popular: GP prescribing of mirtazapine antidepressants now be considered first- low therapeutic doses of escitalopram (for first-line for both first ever and recurrent line choices for depression in primary care? example, 10 mg daily) and non-equivalent episodes of depression has been increasing significantly higher comparator SSRI doses steadily since 2003,3 and by 2017 mirtazapine NETWORK META-ANALYSIS (for example, sertraline 200 mg daily), which accounted for 12% of antidepressant The Cipriani group’s conclusions should are known to lack greater efficacy but are prescriptions in England.10 A 2011 Cochrane be treated with some caution, as they are associated with poorer tolerance and higher systematic review of 29 randomised based on network meta-analysis (NMA). dropout rates.6,7 Conversely, comparator controlled trials comparing mirtazapine NMA methodology enables multiple studies with less effective low-dose (and so directly with other antidepressants found treatments to be compared using both direct non-dual action) venlafaxine (for example, that mirtazapine was superior to SSRIs comparisons within randomised controlled 75 mg daily) may be used to demonstrate at the end of initial treatment over 6 to trials, and indirect comparisons across and claim equivalent efficacy.6 There is 12 weeks.11 Mirtazapine treatment led to a trials based on a common comparator. So, still a relative lack of direct head-to-head similar frequency of dropouts as SSRIs and if antidepressants ‘A’ and ‘C’ have each trial evidence for escitalopram’s claimed tricyclic antidepressants (TCAs), although been compared with antidepressant ‘B’ superiority over other antidepressants, its adverse event profile was unique, directly, you can infer how ‘A’ would perform apart from citalopram.6 characterised by weight gain and sedation compared with ‘C’ through NMA, even if Agomelatine is thought to act through in a significant proportion of patients, but ‘A’ and ‘C’ have never been compared in a combination of antagonist activity at fewer gastrointestinal problems and sexual the same trial. However, the inferences 5HT2C receptors and agonist activity at dysfunction than SSRIs.11 from NMAs that some antidepressants are melatonergic MT1/MT2 receptors, which So how should GPs choose a more effective or acceptable than others makes it unique among antidepressants, as first-line antidepressant for major are not always consistent with direct head- it does not affect the reuptake of serotonin, depressive disorder? The 2009 National to-head comparisons of drugs within trials. norepinephrine (noradrenaline), or Institute for Health and Care Excellence It is therefore important to look also at dopamine. A meta-analysis of direct head- guidance12 and the British Association for systematic reviews of trials comparing to-head studies comparing it with SSRIs Psychopharmacology (BAP)7 suggest an drugs with each other directly. and serotonin and norepinephrine inhibitors SSRI should be considered first, unless This is not the first time Cipriani’s group (SNRIs) found that it had similar efficacy, there is a history of poor response or has suggested that escitalopram should although published trials generally had unacceptable side effects with SSRIs. be a preferred first-line choice due to its more favourable results than unpublished It is important to emphasise that combined higher efficacy and tolerability. trials.8 Given that a year’s treatment costs antidepressant treatment is best avoided In 2009, they published an NMA comparing significantly more, at £390 per annum, than at the initial consultation if possible,13 and 12 antidepressants showing similar fluoxetine (£7), sertraline (£10), escitalopram should only be prescribed if psychological clinically important differences in favour (£14), or citalopram (£13),4 and it requires interventions or exercise have either been of escitalopram and sertraline.2 Following liver function monitoring, agomelatine tried first or are thought to be unsuitable, or the 2009 study, sertraline prescribing rose should currently be limited to a third-line the patient has recurrent depression and is significantly while citalopram prescribing choice. However, it may be considered as a asking for drug treatment, or the patient is levelled off, and that of fluoxetine fell.3 viable alternative when SSRIs, SNRIs, and at risk of developing more severe depression However, escitalopram prescribing did not mirtazapine are all contraindicated. (for example, if they have a history of severe increase significantly.3 That may have been Vortioxetine is a serotonin transporter depression). because escitalopram was still under patent blocker that increases the extracellular There are relatively few differences and was significantly more expensive, but, concentration of serotonin, dopamine, and between SSRIs, although paroxetine is best 114 British Journal of General Practice, March 2019 avoided unless patients particularly ask for is very limited evidence that past or family ADDRESS FOR CORRESPONDENCE it, given its short half-life, which leads to a history is of use in predicting a differential Tony Kendrick 7 greater risk of discontinuation symptoms, response to different antidepressants. Primary Care and Population Sciences, Aldermoor and its greater tendency to cause sexual However, considering patients’ preferences Health Centre, Aldermoor Close, Southampton dysfunction and weight gain. Sertraline is improves treatment adherence and may SO16 5ST, UK. probably a safer choice than citalopram or improve outcomes.7 Email: [email protected] @tony_kendrick escitalopram due to the QTc prolongation Patients should usually be reviewed issue and their potential interactions with, no later than 2 weeks after starting an Tony Kendrick, for example, methadone, antipsychotics, antidepressant (1 week if aged under Professor of Primary Care, Primary Care and and erythromycin, although it causes 30 years or thought to be at increased risk Population Sciences, University of Southampton, more diarrhoea. Important interactions to of suicide), as the risk of self-harm may be Southampton. consider include paroxetine inhibition of increased during the initiation of treatment. tamoxifen; fluoxetine potentiation of the Subsequently, patients can be advised to David Taylor, seizure risk with clozapine; and fluvoxamine Director of Pharmacy and Pathology, Maudsley adjust doses and dose timings themselves, Hospital, and Professor of Psychopharmacology, potentiation of theophylline and clozapine, with a further review at 4 weeks. King’s College London, London. through inhibition of hepatic cytochrome Randomised controlled trials tend to P450 enzymes. recruit highly selected patients without Chris F Johnson, comorbidities, and usually summarise Antidepressant Specialist Pharmacist, NHS Greater PROBLEMS WITH THE SSRIS average treatment effects at the group Glasgow & Clyde Pharmacy & Prescribing Support SSRIs as a class increase the risk of level, rather than investigating potentially Unit, Pharmacy Services, NHS Greater Glasgow & Clyde, Glasgow. gastrointestinal, uterine, and cerebral important modifiers of treatment response bleeding, particularly when taken with at the level of individual patients.1 It aspirin, non-steroidal anti-inflammatories, Provenance is important to emphasise, therefore, Commissioned; externally peer reviewed. or anticoagulants. They should be avoided that there is significant inter-individual by patients with increased risks of bleeding, variation in tolerability and response to Competing