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Home , Agomelatine, Lofepramine, Vortioxetine

Editorials Which first-line ?

Choice of first-line for since patent expiry, generic , and so acts like an SNRI. A 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 inhibitors (SSRIs).4 when it was compared with SNRIs, being to the widely reported meta-analysis by less effective than , although it Cipriani et al in the Lancet, comparing 21 ESCITALOPRAM had less severe adverse effects.9 The review antidepressants for and tolerability.1 So why not choose escitalopram first- criticised a relative lack of direct head-to- They found that , , line? One reason is safety concerns. As head comparisons between and escitalopram, , , with , it can cause significant the SSRIs, and the reliance placed on the , 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 , 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, , , 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 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 activity at dysfunction than SSRIs.11 from NMAs that some antidepressants are 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 . 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 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 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, , , 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 ), 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, risk with ; and 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 . They should be avoided that there is significant inter-individual by patients with increased risks of bleeding, variation in tolerability and response to Competing interests and given together with a protein pump antidepressants, and a flexible, responsive Tony Kendrick and David Taylor are members of the inhibitor for patients with dyspepsia. They approach is usually required to find the right current NICE Guideline Development Group for the are also more likely to cause hyponatraemia, Depression in Adults guideline update. The views treatment for a particular patient. However, expressed are those of the authors and not necessarily especially for patients taking . Rarely, effective treatment is a clinical imperative those of NICE, the NHS, or the Department of Health. concomitant SSRI and use can lead given the morbidity and mortality associated to . For patients with with major depressive disorder. DOI: https://doi.org/10.3399/bjgp19X701405 these relative contraindications, mirtazapine, , or would be a better first choice. Mirtazapine could be REFERENCES a revision of the 2008 British Association 1. Cipriani A, Furukawa TA, Salanti G,et al. chosen if sedation and stimulation of appetite for Psychopharmacology guidelines. J Comparative efficacy and acceptability of 21 Psychopharmacol 2015; 29(5): 459–525. are desired effects, or else a TCA or TCA-type antidepressant drugs for the acute treatment 8. Taylor D, Sparshatt A, Varma S, Olofinjana O. of adults with major depressive disorder: a drug such as nortriptyline or lofepramine, if Antidepressant efficacy of agomelatine: meta- systematic review and network meta-analysis. sedation and weight gain are to be avoided. analysis of published and unpublished studies. Lancet 2018; 391(10128): 1357–1366. Mirtazapine should be titrated up from BMJ 2014; 348: g1888. 2. Cipriani A, Furukawa TA, Salanti G,et al. 9. Koesters M, Ostuzzi G, Guaiana G,et al. 15 mg daily to at least 30mg, as 15 mg Comparative efficacy and acceptability of 12 Vortioxetine for depression in adults. Cochrane may help and symptoms new-generation antidepressants: a multiple- Database Syst Rev 2017; (7): CD011520. in the short term, but is sub-therapeutic treatments meta-analysis. Lancet 2009; for treating major depression.14 SSRIs often 373(9665): 746–758. 10. Prescribing and Medicines Team, NHS Digital. Prescription cost analysis — England, 2017. 3. Kendrick T, Stuart B, Newell C,et al. cause , as do SNRIs and 2018. Table 5: Items by BNF chemicals 2007 to Antidepressants can benefit patients with major TCAs: mirtazapine, , , 2017. https://files.digital.nhs.uk/publication/g/r/ depression, and a 10th key issue is which drugs pca-eng-2007-17-trends-items.xlsx (accessed 4 agomelatine, and vortioxetine are less likely should be used first-line. Br J Gen Pract 2018; Feb 2019). to do so.7 Older TCAs should be reserved DOI: https://doi.org/10.3399/bjgp18X695681). 11. Watanabe N, Omori IM, Nakagawa A,et al. for when first-line treatment has failed, and 4. Regional Drug and Therapeutics Centre Mirtazapine versus other antidepressive agents (Newcastle). Cost comparison charts November monoamine oxidase inhibitors should only be for depression. Cochrane Database Syst Rev 7 2018. 2018. http://gmmmg.nhs.uk/docs/cost_ prescribed by experts. 2011; (12): CD006528. comparison_charts.pdf (accessed 4 Feb 2019). If patients have tried SSRIs for a prior 12. National Institute for Health and Care 5. Medicines and Healthcare products Regulatory episode without response, mirtazapine, Excellence. Depression in adults: recognition Agency. Citalopram and escitalopram: QT and management. CG90. London: NICE, lofepramine, nortriptyline, or an SNRI would interval prolongation. 2014. https://www. 2009, updated 2018. https://www.nice.org.uk/ be a reasonable first choice (venlafaxine or gov.uk/drug-safety-update/citalopram-and- guidance/cg90 (accessed 4 Feb 2019). duloxetine rather than vortioxetine in the first escitalopram-qt-interval-prolongation (accessed 4 Feb 2019). 13. Arroll B, Chin WY, Moir F, Dowrick C. An instance). If they have had no response to evidence-based first consultation for depression: 6. Kennedy SH, Andersen HF, Thase ME. previous treatment with SSRIs, mirtazapine, nine key messages. Br J Gen Pract 2018; DOI: Escitalopram in the treatment of major https://doi.org/10.3399/bjgp18X695681. and SNRIs, then agomelatine would be a depressive disorder: a meta-analysis. Curr Med reasonable choice. Res Opin 2009; 25(1): 161–175. 14. Johnson CF, Williams B, MacGillivray SA,et al. ‘Doing the right thing’: factors influencing GP The BAP guidelines state that useful 7. Cleare A, Pariante CM, Young AH,et al. prescribing of antidepressants and prescribed pharmacogenetic predictors of response to Evidence-based guidelines for treating doses. BMC Fam Pract 2017; 18(1): 72. antidepressants are not available, and there depressive disorders with antidepressants:

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