The Impact of Melatonin in Research

Citation indexes represent helpful tools for evaluating the impact of articles on research. The aim of this study was to obtain the top-100 ranking of the most cited papers on melatonin, a relevant neurohormone mainly involved in phase-adjusting the biological clock and with certain sleep-promoting capability. An article search was carried out on the Institute for Scientific Information (ISI) Web of Science platform. Numbers of citations, names of authors, journals and their 2014-impact factor, year of publication, and experimental designs of studies were recorded. The ranking of the 100-most cited articles on melatonin research (up to February 2016) revealed a citation range from 1623 to 310. Narrative reviews/expert opinions were the most frequently cited articles, while the main research topics were oxidative stress, sleep physiology, reproduction, circadian rhythms and melatonin receptors. This study represents the first detailed analysis of the 100 top-cited articles published in the field of melatonin research, showing its impact and relevance in the biomedical field.


Introduction
By simply typing the word "melatonin" on the PubMed database, more than 1000 records can be easily retrieved, for just year 2015. Melatonin, the main sleep-promoting neurohormone involved in phase-adjusting the circadian clockworks upon prior phase-shifting, recently received overpowering attention in science, medicine and social media, and it is expected to gain even more attention within the near future.
Such a feeling is strongly supported by analyzing the "citation index" of this molecule, i.e. how many times researchers have cited papers on melatonin over time. "Citation index" is, to date, one of the most reliable methods for assessing the quality and the "scientific power" of a paper, a journal or an issue [1], reflecting its impact on research, opening further discussion, producing changes in clinical practice, starting controversy inside scientific community and providing new perspectives in science and in financial funding as well.
The top-100 rank of the highly cited papers provides an interesting picture of the current "hot" topics, even delineating those trends expected to further explode in the future. Along this direction, the rankings of the 100 top-cited articles have been published in a plethora of biomedical disciplines, such as emergency medicine [2], cardiology [3], orthopedic surgery [4] and dentistry [5]. Considering the wide and increasing interest on this hormone, this work aims to provide and analyze the ranking of the 100 top-cited articles on melatonin research.
Unexpectedly, scientific works with limited evidence were cited the most. For the most part, indeed, articles were narrative reviews/expert opinions (33%), followed by basic research/descriptive studies (25%), whilst the less represented papers were systematic reviews (23%) and clinical trials (19%) (Figure 1).  Table 2). The ACR classification also highlighted the work by Galano and colleagues [80] which recorded a very high ACR (=99.7), because their paper, just published in 2011, collected 356 citations.   [13].
Unexpectedly, scientific works with limited evidence were cited the most. For the most part, indeed, articles were narrative reviews/expert opinions (33%), followed by basic research/descriptive studies (25%), whilst the less represented papers were systematic reviews (23%) and clinical trials (19%) (Figure 1).  Because reviews are usually more frequently cited, two different top 10 rankings were created to minimize this bias, in order to evaluate in details the number of citations for reviews vs. original articles (Tables 3 and 4). We included one letter to the editor among the original articles [35], since it reported a novel non-extraction radioimmunoassay (RIA) to detect melatonin in plasma. Interestingly, in both the classifications, melatonin as antioxidant agent and its role in physiology, mainly in regulating mammal reproduction, were the most cited topics.  [20]. 757 Table 4. The top 10 most cited original articles. The golden age for melatonin research, accounting for the largest number of "most-cited" publications, was the 1990-1999 decade, with 35 articles (Figure 2a). This decade also showed the highest number of total citations (18,604, Figure 2b). The 2000s followed with 31 papers and 16,182 total citations. The highest mean of the number of citations, calculated as the total citations from The top 100 most cited articles were published in 52 different journals ( Table 5). The journal with the largest number of papers was Science, with 13 articles, four of them within the first 20. It was followed by the Journal of Pineal Research and Endocrinology, with eight and five papers, respectively. The top 100 most cited articles were published in 52 different journals ( Table 5). The journal with the largest number of papers was Science, with 13 articles, four of them within the first 20. It was followed by the Journal of Pineal Research and Endocrinology, with eight and five papers, respectively. Journal of Pineal Research (9.600) 8 3

Ranking
Endocrinology (4.503) 5 4 Proceedings of the National Academy of Sciences USA (9.674) 4 5 Endocrine Reviews (21.059) 3 6 Journal of Neuroscience (6.344) 3 7 Journal of the National Cancer Institute (12.583) 3 8 Nature ( The Journal of Biological Chemistry (4.573) 2 20 The New England Journal of Medicine (55.873) 2 21 Trends in Pharmacological Sciences (11.539) 2 22 Aquaculture ( Surprisingly, no correlation could be observed between the number of citations in this ranking and the impact factors of the journals where papers were published (linear regression: R 2 = 0.0021, Figure 3). Surprisingly, no correlation could be observed between the number of citations in this ranking and the impact factors of the journals where papers were published (linear regression: R 2 = 0.0021, Figure 3). The authors with the highest number of articles within the rank were Reiter with 16 papers (first author in nine of them), followed by Tan with nine papers (four as first author) and Reppert with six articles (five as first author) ( Table 6). At fourth place, Weaver had five papers and was first Author in one of them. At fifth place, Axelrod, Nobel Prize in Physiology or Medicine in 1970, had five article and he was first author in two of them. Axelrod was ex equo with Manchester.

Discussion
Since the first bibliometrics study on melatonin published two decades ago [110], melatonin has acquired more and more the role of a pleiotropic molecule, regulating each aspect of the biological clock, from sleep to appetite and reproduction. The great impact of this molecule on research is reflected by the highest number of citations corresponding to the 1990s and 2000s. Accordingly, the most frequent topics, found in the top-100 ranking, included sleep physiology, reproduction, circadian rhythms, and oxidative stress. These trends were also reflected by the content of the first ten most cited papers. Nonetheless, melatonin research, to date, covers a number of additional fields, besides the biomedical ones, which are expected to greatly contribute to the further importance of this molecule within the next years. Recently, melatonin has become a relevant issue in plant and food sciences [111,112], but we could not retrieve any specific article among the top 100 rank.
Like any other bibliometric study, our analysis is not exempt from a number of limitations. We are aware that other citation impact measures, not included in our analysis, also exist, such as the hindex, and also we did not control for the effects of self-citation. Additionally, in some cases, the The authors with the highest number of articles within the rank were Reiter with 16 papers (first author in nine of them), followed by Tan with nine papers (four as first author) and Reppert with six articles (five as first author) ( Table 6). At fourth place, Weaver had five papers and was first Author in one of them. At fifth place, Axelrod, Nobel Prize in Physiology or Medicine in 1970, had five article and he was first author in two of them. Axelrod was ex equo with Manchester.

Discussion
Since the first bibliometrics study on melatonin published two decades ago [110], melatonin has acquired more and more the role of a pleiotropic molecule, regulating each aspect of the biological clock, from sleep to appetite and reproduction. The great impact of this molecule on research is reflected by the highest number of citations corresponding to the 1990s and 2000s. Accordingly, the most frequent topics, found in the top-100 ranking, included sleep physiology, reproduction, circadian rhythms, and oxidative stress. These trends were also reflected by the content of the first ten most cited papers. Nonetheless, melatonin research, to date, covers a number of additional fields, besides the biomedical ones, which are expected to greatly contribute to the further importance of this molecule within the next years. Recently, melatonin has become a relevant issue in plant and food sciences [111,112], but we could not retrieve any specific article among the top 100 rank.
Like any other bibliometric study, our analysis is not exempt from a number of limitations. We are aware that other citation impact measures, not included in our analysis, also exist, such as the h-index, and also we did not control for the effects of self-citation. Additionally, in some cases, the number of citations cannot quantify the value of a work contribution to the field [113,114], since this is affected by many bias, mainly temporal ones [115]. Indeed, a paper tends to accumulate citations over time, while recent articles may not have had enough "publication time" to produce high rates in the citation analysis. Conversely, the number of citations may then fall progressively as the content of the paper is absorbed into the current knowledge. Moreover, our methodology was based on the Web of Knowledge platform, referring to all subscribed databases simultaneously consulted for the most comprehensive results. The Web of Science, however, does not index all peer-reviewed journals, thus we might have missed other journals indexed in other databases, such as Scopus. We did not use Google Scholar for this citation analysis, since despite being useful to cover some social and humanities sciences, is not accurate for the biomedical area. It has no quality control, searching within the web for scholarly content and considering, among the others, non peer-reviewed journals, books and academic theses, as well as non-scientific sites, such as promotional ones. The Google Scholar citation index is, thus, not considered highly reliable, at times pre-dating the publication it claims to cite and displaying manifold versions of the same publication, splitting the citation count [116].

Materials and Methods
In February 2016, we consulted Science Citation Index Expanded™, a specific online resource to quantify citations belonging to the Institute for Scientific Information (ISI) Web of Science™ platform [5]. Under "Basic Research" tag, the keyword ("topic") used for search was "melatonin" and all the results were sorted using "time cited -highest to lowest". A second search was then performed under the "Cited Reference Search" tag, using the word "melatonin" as "cited title": every record were checked to identify the most cited ones and matched with the previously obtained list. The number of citations corresponded to the "Citing Article Counts", which referred to all databases and all years, i.e., Web of Science™ Core Collection (1985-present), CABI, CAB Abstracts ® (1973-present), Inspec ® (1969-present), KCI-Korean Journal Database (1980-present), MEDLINE ® (1950-present), SciELO Citation Index (1997-present). We deliberately excluded Google Scholar since it is not purposely intended to retrieve citations in a systematic and controlled way, as Web of Science or Scopus do [116]. The resulting 100 most cited articles were selected and full-text retrieved to verify the coherence with the topic (melatonin in research). The following data were recorded for each one: ranking based on the number of citations; number and names of the authors; year of publication; journal in which published and the corresponding 2013-2014 Journal Citation Report -Science Edition impact factor. The type of article was recorded (review, basic science or clinical trial) as well as methodological design (in vitro study, animal study, case-report, case series, narrative review/expert opinion, observational study, randomized clinical trial, systematic review/meta-analysis). No exclusion criteria were applied. Meanwhile, to further confirm the citation results, the Scopus™ database was also consulted. For each article, the annual citation rate (ACR) was calculated as the ratio between the number of citations (C) and the number of years (Y) since its publication: ACR = C/Y.

Conclusions
Within its limitations, this work highlight and confirms the increasing importance of melatonin, which, in perspective, is expected to significantly regulate the rhythm of future research, with predictable new trends going to be related to biomedical and nutritional sciences.
Acknowledgments: Authors acknowledge all colleagues who studied melatonin and inspired their scientific interest.
Author Contributions: E.V. and M.I. conceived and designed the work, wrote and revised the draft; C.S., R.P. and C.I. performed the search, data analysis, figure and table preparation.

Conflicts of Interest:
The authors declare no conflict of interest.

Abbreviations
The following abbreviations are used in this manuscript: Annual Citation Rate (ACR) Journal of Citation Report (JCR) Institute for Scientific Information (ISI)