Introduction
Depressive disorders affect approximately 12% of the Irish population and are a leading cause of disability worldwide.^1,2 Successful management of depression requires a bio-psycho-social approach. The majority of medications used to treat depression target the mono-aminergic system but clinical trials show that a third of patients fail to improve despite use of these drugs.³ Agomelatine is an agonist at melatonin receptors, which are involved in the maintenance of circadian rhythms.⁴ Clinical trials of agomelatine have demonstrated its efficacy as an antidepressant, but have also shown increases in liver function tests (LFTs) associated with its use. In 2009, the European Medicines Agency (EMA) granted marketing authorization for agomelatine for major depression with the recommendation that LFTs are checked before, and 6, 12 and 24 weeks after, commencing treatment with the drug.⁵ Recommendations such as these require physicians’ adherence if patient safety is to be optimized. In this study, we describe clinical experience with agomelatine and audit physician adherence to the EMA recommendations in the first year post licensing.
Methods
The study involved patients attending general adult psychiatry services in Carlow /Kilkenny (catchment population 120,000). An electronic search of patient records retrospectively identified those prescribed agomelatine between January and December 2010. Data were collected on demographic details, working diagnoses and other medications prescribed. Local laboratory systems, case notes and correspondence with GPs for each patient were searched and the frequency of LFT measurements in a 6 month timeframe determined.
Results
62 patients were prescribed agomelatine; ages ranged from 18 to 70years (median 42years) and 48 (77%) were female. The most common diagnoses were depression (n=32, 52%), mixed anxiety / depression (n=14, 23%) and bipolar affective disorder (n=8, 13%). Agomelatine was added to other antidepressants in 45 patients (73%), to anti-psychotics in 28 patients (45%) and to lithium in 6 patients (10%). LFTs were recorded before commencement of agomelatine in 97% of cases. Of those still taking the medication, 53% had repeat LFTs checked at 6 weeks, 36% at 12 weeks, and 46% at 24 weeks (Figure 1). No serious adverse events or significant elevations in LFTs were seen.

 

Discussion
In this study, patients commenced on agomelatine were a heterogeneous group; many were already on multiple psychotropic medications including other antidepressants. Although screening of baseline LFTs was good, approximately half did not have further LFT monitoring as advised. There are a number of possible explanations for these findings. Firstly, poor awareness of the EMA recommendations is likely given agomelatine’s recent licensing. Awareness and adherence to monitoring can be increased by printing recommendations on drug packaging, such as the ‘black box warnings’ issued by the Food and Drug Authority (FDA) in the US.⁶ The maximum legal duration of any prescription in Ireland is six months. The need for a repeat prescription could be utilized as a trigger to assess the need for LFTs, and could be facilitated by the use of computerised prompts to physicians.⁷ Secondly, effective drug monitoring requires both physician adherence in ordering the test and patient adherence in attending for the test.⁸ It is unclear from this study if patient non-attendance contributed to the low level of follow-up LFTs. Increasing patient education on the importance of monitoring may help improve levels of adherence with recommendations.

Lastly, patients in this study were commenced on agomelatine by specialist services, but were followed up by their general practitioners (GPs). Correspondence to GPs regarding initiation of the drug and the requirement for LFTs may have been sub-optimal. The lack of consensus on who should perform follow-up laboratory monitoring (GP or specialist) may also have had an impact. Improved communication between primary and secondary care will help to address these issues. Community pharmacists may also have a role to play, by ensuring monitoring has been performed prior to dispensing. Although the safety profile of agomelatine in this study was good, our data is limited by small numbers, short follow-up and retrospective collection. A Cochrane review on agomelatine versus other antidepressants in major depression is currently underway, and will clarify the role of the novel antidepressant more accurately.⁹


Correspondence: C Sinnott
Department of General Practice, University College Cork, Cork
Email: [email protected]

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