The presented analysis of naturalistic observational data provides important epidemiological data in a large number of non-selected patients (n = 9601). The findings demonstrate the effectiveness and good tolerability profile of agomelatine, which is in line with proven efficacy and tolerability in various RCTs [21, 26]. In the observational VIVALDI study [31] this effect was also demonstrated independent of psychotropic co-medication, which is confirmed in the presented mixed patient cohort.
Demographic data of the evaluated depressed population are representative of daily medical care with a high proportion of pretreated and comorbid patients [37]. Severity of depression was more pronounced in patients treated by specialists, reflected by the proportion of psychiatric comorbidities, co-medication, number and duration of depressive episodes as well as previous suicide attempts.
More than two-thirds of this large sample used agomelatine 25 mg/day (1 tablet) over 12 and 24 weeks, being in line with controlled data where about 75% of patients were medicated with 25 mg/day [38]. A dose increase in the presented patient cohort was documented more frequently by psychiatrists compared to GPs (VIVALDI Praxis), possibly as a result of more pronounced severity of depression and higher incidence of psychiatric comorbidities and co-medication in specialists’ practices.
In the present analysis, the CGI scale was used as an indicator for effectiveness, representing a general assessment of severity and improvement of depression by physicians. The CGI usually corresponds well with treatment effects evaluated with more specific scales (MADRS, Montgomery-Asberg Depression Rating Scale; Hamilton Depression Scale, HAM-D) in clinical and observational studies [31, 38, 39]. In the VIVALDI and VIVALDI Praxis trials, the short version MADRS (svMADRS) [40] was used in addition to CGI and confirmed CGI results, also being comparable to RCT data. Improvement according to CGI in our sample can therefore be seen as an indication for effectiveness of agomelatine with response and remission rates supporting the results of controlled data [38, 39]. Moreover, the antidepressant effect in this outpatient setting can also be evaluated in the continuation and maintenance phase of treatment, representing meaningful information in addition to clinical trials over 6–12 weeks, owing to a placebo control arm being included.
The overall incidence of ADRs in our unselected patient population is low with a known profile of adverse events (especially headache, nausea, dizziness). No new information was obtained about previously unknown ADRs compared to the existing database of controlled trials or non-interventional studies. Most ADRs/sADRs were documented within the first weeks of treatment and markedly decreased after 12 weeks. sADRs were no longer reported after week 24. Interestingly, ADRs and sADRs occurred nearly independent of psychotropic co-medication. Taken together, the presented results confirm data of clinical trials considering tolerability without effects on sexual function or cardiovascular parameters and a favorable interaction profile with emergence of ADRs primarily at the beginning of treatment [11].
In our large sample, no relevant changes of body weight occurred during short-term treatment or over 24 weeks. These results are in good agreement with possible positive metabolic effects of agomelatine described in several studies [41, 42]. A specific receptor profile without affinity to other receptors (especially no anti-histaminergic effect), normalization of circadian rhythms by melatonergic effects, and a positive influence on cortisol levels could serve as an explanation. These characteristics of the substance seem relevant, since weight gain is a frequently observed undesired effect with psychotropic medication [43].
In order to investigate the influence of agomelatine treatment on liver function, transaminase values were documented in all four studies. For the present pooled analysis, transaminase values (ALT/AST) were available for about half of the patients at every visit and for about two-thirds of all patients at baseline and at least one further follow-up visit. Comparison of the included individual studies confirms the assumption that transaminase monitoring is performed more often by GPs compared to psychiatrists. Besides, the increasing proportion of documented transaminase values over time between 2009 and 2013 is shown, presumably correlating with increasing awareness of physicians concerning transaminase monitoring in agomelatine-treated patients. Overall, clinically relevant elevations of ALT and/or AST (>3× ULN) were documented for 49 patients (0.5%), 19 (0.2%) of whom already showed elevations before the beginning of medication, hence not being classified as ADR. Transaminase values generally normalized after discontinuation of agomelatine, in some cases even during continuation of treatment, which is in line with RCT data [22, 23, 44]. One patient with symptoms of hepatitis and icterus recovered without any further impairment after discontinuation of treatment. A detailed case description has previously been published [36]. Before treatment initiation, only incomplete laboratory values were available for this patient, further supporting the importance of transaminase monitoring before medication, and thereby improving risk detection of preexisting impaired liver function. It is worth mentioning that no case of acute liver failure occurred under controlled conditions with strictly requested blood tests in RCTs in nearly 8000 patients [44].
Presented pooled data show a lower incidence rate of clinically relevant elevations compared to numerous controlled trials [11, 22, 23, 44]. Recruitment practice could possibly account for a higher incidence in RCTs, especially compared to American studies with more patients having preexisting risk factors (e.g., hepatobiliary disorder) [23, 45]. Strict clinical monitoring under controlled conditions could also explain higher reporting rates in RCTs compared to this naturalistic design. The demonstrated lower incidence in this pooled data set, however, is verified by an additional analysis based on patients with available values at every visit (ALT, n = 5061; AST, n = 4956). This additional calculation (comparable to “per protocol” analysis) confirms lower incidence rates of transaminase elevations (ADRs) in 23 patients corresponding to 0.46% and of all documented cases including preexisting baseline elevations with 0.98% (n = 49).
Various database analyses have been published so far, investigating spontaneous reports of adverse hepatic effects during agomelatine treatment [46,47,48], to explore quantitative signals about reporting frequencies without causality assessments, since reports listed in safety databases are “raw data” [49]. Gahr and colleagues describe that hepatic effects in agomelatine-treated patients (mostly asymptomatic transaminase increase) occur primarily in the initial phase of treatment. Polypharmacy, female gender, and age over 50 years were described as possible risk factors [46].
Our results confirm the emergence of transaminase elevations within the first weeks of treatment, reversibility, and increased occurrence in women and patients with co-medication. Older age, however, did not correlate with higher risk of transaminase abnormalities in our population with two-thirds of the patients being younger than 55 years.
This result is confirmed by RCT data, demonstrating good tolerability in older patients up to 6 months of treatment [50, 51] without the necessity for dose adjustment in elderly patients [11]. Higher incidence of transaminase elevations in women within this sample could possibly be explained by the high proportion of women in the depressed population in general. Nevertheless, even taking baseline data into account with a ratio of 2:1 (female/male), the presented results still show a trend for a higher frequency in women.
With the objective of ensuring therapeutic safety, the European Medicines Agency (EMA) has developed increasingly rigorous criteria regarding quality of studies and especially pharmacovigilance procedures. Regular monitoring of various blood tests, ECG (electrocardiogram), EEG (electroencephalography), or other controls are required or recommended for many antidepressants or psychotropic drugs in guidelines, standard references, and textbooks [37, 47, 52, 53].
In this context, monitoring of hepatic transaminases is listed in the SmPC of agomelatine and should be performed before the initiation of treatment, after approximately 3, 6, 12, and 24 weeks, after emergence of clinical symptoms of hepatic dysfunction, and after a dose increase [11].
Considering the general risk of possible drug-related liver damage during treatment with psychotropic drugs, monitoring of liver function tests is recommended in general [11, 37, 47, 52, 54, 55]. Thereby therapeutic safety as well as early detection of patients at risk with preexisting relevant diseases can be improved, especially in case of polypharmacy [37, 52, 54,55,56,57].
Limitations
An important limitation to be mentioned is the non-interventional, open-label, observational design of the four individual studies included in the present pooled analysis, with lack of randomization, blinding, and placebo control group. Therefore the observational design might lead to an overestimation of therapeutic effects compared to RCTs. Controlled studies with strict inclusion/exclusion criteria, however, do not represent naturalistic patient populations with comorbidities and co-medication, which underlines the relevance of non-interventional studies. Even though observational trials are not able to provide proof of efficacy because of methodological reasons, they nonetheless provide important information of everyday clinical practice. The notable strength of the presented pooled analysis is the large number of non-selected patients.
Potential underestimation of adverse drug reactions due to possible underreporting can not be completely ruled out. As a result of the non-interventional design, ADRs were not assessed systematically but were documented in the form of open questions at each visit. Considering data of controlled studies, however, type, severity, and time of emerging ADRs within our presented pooled data are in line with the tolerability profile demonstrated in RCTs.
Short duration of individual studies over 3 months is a further limitation worth being discussed. The main analysis of pooled data was performed after 12 weeks, thereby representing short-term treatment. However, this correlates well with the duration of RCTs between 6 and 12 weeks. Besides, a subgroup over 24 weeks with more than 3000 patients was additionally analyzed in this pooled dataset, providing relevant data for continuation treatment in unselected patients.
Another limitation to be mentioned is the mixed nature of data due to significant differences in investigators. In the presented pooled analysis the treatment effect of agomelatine has been evaluated rather generally by means of the CGI as a less specific scale compared to more detailed scales used in psychiatry. Besides, GPs in VIVALDI Praxis were offered a rater training (like psychiatrists in the VIVALDI study) via a video test version of the more complex svMADRS questionnaire to ensure a high quality of collected data. Concerning the analysis of tolerability, the specialization of doctors should probably generate only minor differences. According to the objective of gaining information about psychiatric care in daily routine, the strength of the actual pooled analysis is the large sample of comorbid and co-medicated patients of daily practice, as in German psychiatric care the intersectoral treatment situation between hospital care and outpatient treatment (by specialists and/or GPs) is an actual and important issue.
As a result of possible differences in the point of view on psychiatric disorders between the two groups of physicians, separate results for psychiatrists and GPs would have been informative. In conformity with the statistical analysis plan (SAP) and the stated objective of analyzing a large sample of naturalistic psychiatric patients as an overall group, stratified data analysis according to doctors’ specialization has not yet been performed. However, baseline data, dosage, and evolution of depressive symptoms by means of CGI are presented in the total population and on the basis of individual studies, thereby allowing a first insight into this interesting question. Further evaluation of this large database with a focus on stratification could offer an additional objective for a prospective data analysis.