Melatonin and Melatonin Agonists as Adjunctive

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Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders Pierre Alexis Geoffroy1,2,3,4*, Bruno Etain4,5,6,7, Jean-Arthur Micoulaud Franchi8,9, Frank Bellivier1,2,4,10 and Philipp Ritter11 1

INSERM, UMR-S 1144, Paris, 75006, France; 2AP-HP, GH Saint-Louis - Lariboisière - Fernand Widal, Pôle Neurosciences, 75475 Paris Cedex 10, France; 3Université Paris Descartes, UMR-S 1144, Paris, 75006, France; 4 Fondation FondaMental, Créteil, 94000, France; 5AP-HP, Hopitaux Universitaires Henri Mondor, DHU PePsy, Pôle de Psychiatrie, Créteil, 94000, France; 6INSERM, U955, Psychiatrie génétique, Créteil, 94000, France; 7 Université Paris Est Créteil, Créteil, 94000, France; 8Services d'explorations fonctionnelles du système nerveux, Clinique du sommeil, CHU de Bordeaux, 33076 Bordeaux; 9USR CNRS 3413 SANPSY, CHU Pellegrin, Université de Bordeaux, France; 10Université Paris Diderot, UMR-S 1144, Paris, 75013, France; 11Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstraße 74, 01307 Dresden Pierre Alexis Geoffroy

Abstract: Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD.

Keywords: Bipolar disorders, Melatonin, Ramelteon, Tasimelteon, Sleep, Circadian rhythms. INTRODUCTION Bipolar disorder (BD) is a severe psychiatric disorder characterized by recurrent manic and depressive episodes that affect 1% to 4% of the general population worldwide [1]. BD is ranked as one of the most burdensome diseases globally due to its peak age at onset in adolescence and early adulthood, consequently leading to poor functioning and diminished quality of life throughout adulthood [24]. BD has a complex inheritance pattern implicating both genetic and environmental factors, with increasing evidence that abnormalities of circadian rhythmicity and sleep homeostasis contribute to the underlying neurobiology of and genetic susceptibility to BD [5, 6]. Indeed, these abnormalities are part of the diagnostic criteria for the acute phases of BD, with the classic patterns being the presence of insomnia or hypersomnia during major depressive episodes and a decreased need for sleep without subsequent fatigue in (hypo)manic episodes [7, 8]. It is now recognized that BD cases experience pervasive sleep and circadian abnormalities during remission phases (i.e. when no or minimal other bipolar symptoms are present) [9]. Firstly, 83% BD patients in remission reported poor sleep quality compared to 21% of healthy controls [10] and Harvey et al. observed that 55% BD cases also met diagnostic criteria for insomnia [11]. Insomnia is thus a frequent comorbidity of BD. Secondly, BD patients exhibit *Address correspondence to this author at the Service de Psychiatrie Adulte (Pr. Frank BELLIVIER), Groupe Hospitalier Saint-Louis-LariboisièreFernand Widal, 200 rue du Faubourg Saint Denis, 75475 Paris Cedex 10 France; Tel: +33 (0) 1 40 05 48 69; Fax: +33 (0) 1 40 05 49 33; E-mail: [email protected] 1381-6128/15 $58.00+.00

circadian abnormalities with evening chronotype [12] and more than 60% of young patients with BD when depressed presented with a delayed sleep phase, compared with 30% of those with unipolar depression and 10% of control participants [13]. And thirdly, sleep parameters (in particular sleep onset latency, total sleep time and sleep efficiency) are abnormal in patients with BD [9, 14]. Sleep and circadian abnormalities during the remission period are associated with mood relapses as well as functioning, quality of life and metabolic syndrome [15-17]. Therefore, sleep and circadian abnormalities in BD have been considered as possible therapeutic targets using chronobiotic drugs [18, 19]. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses [20]. Melatonin secretion is nocturnal and influenced by photoperiod (dark-light periods), with its synthesis determined by the activity of the serotonin Nacetyltransferase (AANAT) enzyme in a reaction that requires acetyl coenzyme A (AcCoA) [21]. Exogenous melatonin has demonstrated efficacy with both objective (polysomnography or actigraphy) and subjective measures (scales, questionnaires, sleep logs) in: i) treating primary insomnia in adults and children in numerous trials [22, 23], ii) treating patients with delayed sleep phase disorder [24], iii) improving sleep parameters (sleep onset latencies and total sleep time) and overall sleep quality [23], and iv) improving some sleep and behavioural disorders in children with autistic spectrum disorders (ASD) [25-27]. The whole of these proofs of efficacy of exogenous melatonin is strongly in favor of its possible interest of use in patients with BD. © 2015 Bentham Science Publishers

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AIMS OF THIS REVIEW In order to evaluate the efficacy of melatonin in BD, this comprehensive review aimed to examine 1) abnormal melatonin function in BD, 2) the rationale for a potential melatonin therapeutic action in BD, 3) the available data on the use of exogenous melatonin, as well as the use of ramelteon and of tasimelteon (two melatonin receptor agonists), and 4) some considerations about how to use it in practice. METHODS Search Strategy A literature search using PubMed, ISI Web of Knowledge and the Cochrane Library was performed. Publication year was restricted to 1970 or later. No country restrictions were used. The search term used for the electronic database search was: (Melatonin OR Melatonin Treatment OR Ramelteon OR Tasimelteon OR Melatonin Agonist) AND (bipolar disorder OR bipolar disorders OR manic-depressive illness). The latest search was performed in October 2014. Study Selection Two authors (PAG and PR) reviewed the title and abstracts of publications identified through databases to identify eligible studies. The two authors independently and then jointly selected studies for detailed extraction based on the full text. Studies were eligible only if original data were reported on the use of exogenous melatonin, ramelteon or tasimelteon in patients diagnosed with BD. We excluded agomelatine from the present review because of the plural properties of this drug that associates both agonist actions at melatonergic receptors but also antagonist actions at serotonergic 5HT2C receptors [28]. Reference sections of the publications found through our electronic search were manually checked to identify additional studies that may have been missed. RESULTS Abnormal Melatonin Function in BD BD patients during remitted phases are supersensitive to melatonin suppression by light [29-33], which has been proposed as a “trait” biomarker of BD, given its independence of patients’ mood state, strong heritability and increased prevalence with increased familial genetic load [33, 34]. Interestingly monozygotic and dizygotic twins studies showed that both overall melatonin levels and suppression by 500-lux of light have a strong genetic component [33]. We have identified few studies that found no melatonin suppression by light in patients with BD by comparison with healthy controls [35, 36]. Consistent with the existence of an abnormal light suppression melatonin function, some evidence indicate the existence of abnormal concentration and periodicity of nocturnal melatonin secretion in particular in euthymic patients with BD I subtype (significantly lower melatonin levels at baseline and following light exposure of 500-lux light administered between 2 and 4 AM, as well as a later peak time for melatonin on the dark night) [29]. Furthermore, these abnormalities appear more prominent in patients with BD compared to unipolar depression [13]. Although melatonin onset abnormalities are associated with BD, some discrepancies are observed in the literature regarding the exact nature of the change [37]. During daytime, patients during episodes of mania, compared to bipolar patients suffering from depression and to controls, appear to present with elevated melatonin levels [38]. This study observed the most important changes during the afternoon and evening hours, when the melatonin levels were elevated to nearly half of the maximal nocturnal levels [38]. This changed did not appear to be due to a phase advanced. These findings confirmed a previous case study observing elevated levels of melatonin during mania [39].

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However, since these findings are not consistent with previous studies that found decreased serum melatonin levels compared with controls and no significant differences between manic and depressive episodes compared to euthymic phases [29-33], they might highlight rather a disruption of temporal melatonin regulation in BD compared to controls. This hypothesis, if confirmed, might also explain disruptions demonstrated in the diurnal expression patterns of several clock genes [38, 40]. From an anatomic point of view, no difference in the total pineal volume responsible of the melatonin secretion, has been observed between patients with BD and healthy subjects [41]. Genetic studies indicate that a common polymorphism (rs4446909) of the promoter of the acetylserotonin O-methyltransferase (ASMT) gene, encoding one of the two enzymes involved in melatonin biosynthesis, was associated with BD and presented with weaker transcription and lower levels of ASMT activity [42]. Interestingly this BDassociated functional variant, involved in the melatonin synthesis pathway, was examined with actigraphy in remitted patients with BD and healthy controls, and demonstrated to influence sleep and circadian rhythms [43]. In summary, functional abnormalities rather than abnormal pineal gland volume are likely to explain melatonin secretion abnormalities in BD. These functional disruptions may include functional gene polymorphisms in melatonin biosynthesis key enzymes, supersensitivity to melatonin suppression (trait marker) and temporal deregulation of melatonin profiles during mood states, and especially during manic episodes (state marker). Rationale of Melatonin Action in Mood Disorders Indirect evidence suggests that melatonin may play a role in the mood stabilizers therapeutic action in patients with BD [44]. Lithium, demonstrated to act on the nocturnal melatonin peak and to modify the function of the retinal-hypothalamic pineal pathway [45]. Lithium and valproate, have demonstrated to act on the melatonergic system by reducing melatonin suppression in response to light in healthy volunteers [46, 47]. Some of the efficacy of valproate may be mediated by the increase of melatonin receptors in C6 glioma cells and in the hippocampus of the rat brain [48]. Further, this mood stabilization through circadian and sleep stabilization is consistent with symptoms preceding the onset of mood episodes. For manic episodes for example, many psychological, environmental and pharmacological factors may influence mood stability by causing sleep deprivation [49]. Sleep alterations are also the most common early symptom preceding manic episodes [17] and the behavioral stabilization of social and sleep rhythms has been demonstrated to prevent relapses in patients with BD [50]. Finally, since BD is associated with various immune-inflammatory abnormalities [51], anti-inflammatory and immune regulatory effects of melatonin would also be possibly relevant in these patients [52]. From a molecular perspective, melatonin may act by stabilizing circadian rhythms of neurotransmitters systems involved in the pathophysiology of BD and associated with rhythmic deregulations. Serotonergic, dopaminergic and noradrenergic neurotransmissions regulate mood and follow circadian variations regarding their secretion, catabolism and receptors [53]. In the pineal gland, close connections between serotonin and melatonin exist. The main one is the secretion of melatonin that directly comes from the catabolism of serotonin, synchronized and regulated by the “the master circadian pacemaker” that is located in the suprachiasmatic nuclei (SCN) [54]. Measures of the concentration of serotonergic neurotransmitters and their metabolites in cerebrospinal fluid (CSF) are considered among the most valid methods of assessing central nervous system function in man [55]. It has been observed that, levels of tryptophan (TRP) and 5-hydroxy indoleacetic acid (5HIAA) -serotonin’s metabolites- are associated with significant biological variability during the 24 hours period. Furthermore, TRP increased levels at night and diminished levels at mid-day [55].

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Finally, pharmacological and not physiological doses of melatonin have shown to inhibit serotonin uptake by platelets [56]. It has long been demonstrated that Dopamine has multiple roles related to circadian rhythmicity as a chemical messenger for light adaptation in the retina [57]. Indeed, amacrine cells release dopamine that activates dopamine receptors distributed throughout the retina. These modulate melatonin secretion via the retinalhypothalamic-pineal pathway [57]. Regarding noradrenergic neurotransmission and its interactions between circadian and mood functions, it has been demonstrated that maximal concentrations of pineal AANAT and melatonin were related to changes in the activity of pineal beta adrenergic receptors, the stimulation of which by noradrenaline is necessary for pineal melatonin synthesis [58]. Later, the pivotal role of noradrenaline in the stimulation of melatonin synthesis has been confirmed in cellular and molecular studies [59]. Taking together, these findings suggest that melatonin levels and circadian rhythmicity of melatonin secretion are closely interconnected with serotonergic, dopaminergic and noradrenergic neurotransmissions regulating mood along the retinal-hypothalamicpineal pathway. However, to what extend the melatonin potential therapeutic action in BD rely on the modulation of serotonergic, dopaminergic and noradrenergic neurotransmissions deserve further investigations. Melatonin as an Adjunctive Treatment in BD? From the comprehensive literature search, five publications were retrieved on the exogenous administration of melatonin, two on the administration of ramelteon and none on the administration of tasimelteon. No study about controlled/prolonged-release melatonin or tasimelteon in BD was identified. Melatonin The first case report on the usefulness of exogenous melatonin for treating bipolar disorder was published in 1997 [60]. A 10 year old boy with a severe form of bipolar disorder including recurring psychotic episodes and episodic severe insomnia had been treated with various mood stabilizers including lithium, valproic acid, antipsychotics and carbamazepine which had to be discontinued due to a lack in therapeutic effect or severe side effects. Discontinuation of all other medication and initiation of melatonin at initially 3mg and later between 6-12mg led to a considerable reduction in psychiatric symptoms and sleep disturbance. A later case report used melatonin 3 mg as an adjunctive treatment with buspirone 5mg and bupropion 75mg, added to lithium and lamotrigine (ineffective alone), and observed an efficacy in treating resistant bipolar depression [61]. Two subsequent studies on case series were then published. Leibenluft et al. administered 10mg of melatonin at 10.00 pm to five patients with rapid-cycling bipolar disorder for twelve weeks. The study had a double blind, randomized and balanced cross over design [62]. The exogenous administration had no significant effects on either mood or sleep parameters. In an open and non-controlled trial Bersani et al. used 3mg of melatonin to treat insomnia in 11 bipolar patients who presented with acute mania for the duration of one month [63]. At the endpoint, sleep duration had improved from 2.43 hours (SD=0.76) to 5.24 hours (SD=1.51) and manic symptoms, as determined by the Brief Psychiatric Rating Scale (BPRS), had decreased from 22.72 (SD=4.45) to 14.09 (SD=4.43). More recently Romo-Nava et al. administered 5 mg of melatonin to 20 patients with bipolar disorder in an eight-week, double blind, randomized, placebo-controlled trial [64]. The study primarily aimed at assessing the effect of melatonin on metabolic parameters in patients with schizophrenia or bipolar disorder receiving second-generation antipsychotics. Mood was recorded as a secondary outcome parameter. Administration of melatonin was not significantly superior to placebo in its effect on depressive symptoms

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as measured with the Hamilton Depression Rating Scale (HAMD) (mean reduction placebo = -4.7; mean reduction melatonin = -3.1; F=0.1; p=0.75) or manic symptoms as measured with the Young Mania Rating Scale (YMRS) (mean reduction placebo = -3.7; mean reduction melatonin = -4.5; F=0.06; p=0.79). Ramelteon The first study to assess the use of ramelteon, a melatonin receptor agonist, in bipolar disorder was published in 2011 by McElroy et al. [65]. In a double-blind, controlled trial of 21 patients suffering a manic episode and diagnosed with bipolar disorder, 8mg of ramelteon was compared to placebo. The study medication was administered in addition to ongoing anti-manic treatment. After eight weeks of treatment no benefit of ramelteon on sleep parameters as measured with the Pittsburg Insomnia Rating Scale (PIRS) or the Pittsburg Sleep Quality Index (PSQI) could be demonstrated. There was also no significant effect on manic symptoms as measured by the YMRS. However, ramelteon decreased depressive symptoms in these patients, and was well tolerated with no serious adverse events [65]. The efficacy of ramelteon in reducing relapse-rates in euthymic patients with bipolar disorder and suffering from symptoms of insomnia was studied by Norris et al. [66]. Eighty-three patients who were currently in remission (MADRS12, YMRS12) but experienced difficulties sleeping (PSQI5) were randomized to receive 8mg of ramelteon or placebo in addition to ongoing treatment for a total of 24 weeks. Ramelteon was superior to placebo in terms of relapse rate (OR=0.48; p=0.024) and median duration until relapse (ramelteon=188 days, placebo =84 days; p=0.002). There were marginally significant effects on depressive symptoms favouring ramelteon but no significant effects on sleep as determined by the PSQI. Ramelteon appeared to primarily act on the prevention of depressive and mixed episodes, with no difference in the development of manic episodes. Recommendations of Use in Patients with BD Although, open studies and meta-analyses support the use of melatonin in primary insomnia [22, 23], in sleep parameters [23] and delayed sleep phase disorder [24], there is no sufficient high quality studies to support the recommendation of the use of melatonin in BD. However, patients with BD during remission periods exhibit insomnia [11], persistent sleep abnormalities [9] and evening chronotype (preference for going at bed late in the evening) with abnormal circadian rhythms [12]. Some data suggest that melatonin may improve these sleep abnormalities in BD, although the evidence is inconsistent. There is promising data on the use of the melatonin agonist ramelteon to prevent relapse episodes. The study data indicates that the mechanism maybe beyond a simple improvement in the quality of sleep Fig. 1. Lessons can be drawn from studies in non-BD samples. In samples with primary insomnia, melatonin demonstrated significant efficacy in reducing sleep latency, increasing total sleep time and improving overall sleep quality. Studies used regimens from 0, 5 to 5 mg from 7 to 182 days. Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time [23]. Other lessons come from the meta-analysis of the efficacy of melatonin in delayed sleep phase disorder (DSPD) [24]. Melatonin treatment advanced mean endogenous melatonin onset by 1.18 hours and clock hour of sleep onset by 0.67 hours. Melatonin also decreased sleep-onset latency by 23.27 minutes. Studies performed in adults included various regimens of administration of melatonin: dose ranging from 0, 3 to 5 mg, duration between 2 and 4 weeks, and various times of administration (from 17h00 to 22h00) [24]. Considering these two meta-analyses, the recommended dose of melatonin in patients with BD would be between 0, 3 to 5 mg per administration. Guidelines about DSPD recommend that exogenous

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Fig. (1). Rational for melatonin use in bipolar disorders. Continuous line: evidence-based associations; Dotted line: suggested associations with few data.

melatonin should be administrated between 1.5 and 6.5 hours prior to the DLMO for four weeks (DLMO is the so-called dim light melatonin onset, in physiological conditions endogenous melatonin starts to rise in dim light i.e. normally between 19: 30 and 21: 30 in adults) [67]. Although there is no strong evidence, the later metaanalysis on melatonin in DSPD proposed an administration that could be also started at bedtime and progressively advanced earlier in the evening if the patient has delayed sleep phase [24]. We cannot provide any recommendation regarding the duration of treatment in BD. Finally, when treating DSPD in BD, others psychiatric comorbidities such attention deficit hyperactivity disorder, seasonal affective disorders, anxiety disorders and comorbid substance use disorders are also associated with DSPD and so should be systematically screened [68, 69]. Regarding the use of melatonin as adjunctive treatment during remission phases, there is a lack of randomized controlled trials (RCT). However it seem clinically relevant to try melatonin in case of comorbid chronic insomnia, delayed phase disorder, and abnormal sleep quality. Treatment of insomnia and delayed phases disorder might have a prophylactic action since persistent sleep disorders and abnormalities are predictors of mood relapses [15-17]. Furthermore, one out of two available trials with a randomized controlled design has demonstrated a significant reduction in time until relapse with ramelteon [66]. The recommended dose would be 8mg applied to patients who are currently in remission. Ramelteon is currently available in the US but not in Europe. Regarding the use of melatonin as adjunctive treatment during acute phases of BD (manic or depressive), there is also a lack of RCT. Some arguments exist in favor of the usefulness of melatonin in manic episodes [63] and of ramelteon in patients with BD during depressive episodes [66]. Nevertheless, this is counterbalanced by the absence of significant effect of melatonin in the recent meta-analysis of Hanse et al. that found no prophylactic effect of melatonin against depression in patient without and with antecedent of unipolar depression [70].

DISCUSSION This literature review suggests preliminary evidence that melatonin - as an adjunctive treatment - can be effective in improving insomnia, sleep quality and delayed sleep latency in BD, but the data on the treatment of acute phases and mood stabilization are inconclusive. However, the only RCT of ramelteon demonstrated a significant improvement in time until next episode. This review highlights the urgent need for good quality RCT of melatonin and melatonin agonists in BD, both during acute phases (depression and mania) and for relapses prevention (through a potential improvement of sleep quality and stabilization of circadian rhythms). An additional interesting adjunctive therapeutic effect might be on metabolic syndrome in BD patients treated with antipsychotics. Indeed, Melatonin recently demonstrated to prevent the adverse metabolic disturbances in second-generation antipsychotic (SGA)treated patients in patients with BD and schizophrenia: decrease in diastolic blood pressure, mean fat mass and triglycerides [64]. Interestingly this effect was particularly observed in patients with BD as compared to schizophrenia [64]. These results have also been confirmed in adolescent with BD for which the administration of melatonin along with olanzapine and lithium carbonate demonstrated to inhibit the rise in cholesterol and triglyceride levels, and systolic blood pressure compared to placebo [71]. These data are supported by previous pre-clinical findings that showed a melatonin action in reducing weight gain in rats [72-74]. Melatonin have also demonstrated action in the regulation of metabolic processes including insulin, leptin, and lipid regulation [75-77]. Further, a similar efficacy was demonstrated of the prevention in the body weight increase in SGA-treated rats [78]. Melatonin affects sleep propensity as well as the duration and quality of sleep and a dose ranging from 2 to 5 mg is effective in patients with insomnia and in patients with delayed sleep phase disorder [24, 79]. Further, melatonin and melatonin agonists have little dependence potential in contrast to most available sleep medications, is not associated with habituation and no hangover. These

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circadian rhythms and sleep effects, and relatively benign sideeffect profile are explaining the wide use of melatonin in the United States [79]. During pregnancy, melatonin - that is increasingly produced by the placenta over the course of pregnancy- might be also a useful and safe supplement, especially in the later stages, and would possibly decrease the likelihood of post-partum depression and psychosis in women with BD [80]. CONCLUSION Preliminary data suggest that melatonin and melatonin agonists may be useful for improvement of sleep quality and relapse prevention in BD. Abnormalities in circadian rhythms and sleep homeostasis are prominent features of BD. Present data emphasize the potential usefulness of melatonin as an adjunctive treatment to mood stabilizers in treating sleep disorders in BD and of ramelteon to prevent relapses when administered during remission phases. We emphasize the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD since such disturbances are possible triggers of future relapses and prodromal markers of an emerging mood episode. However, further studies are needed to produce evidencebased therapeutic guidelines supporting the routine use of melatonin or melatonin agonists in the treatment of BD. AUTHORS’ CONTRIBUTIONS PAG, BE & PR designed the review. PAG & PR performed the literature search and studies selection. PAG, BE, JAMF, FB & PR participated in the results interpretation, the manuscript redaction and approved the final version of the manuscript.

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CONFLICT OF INTEREST The authors declare no conflict of interest.

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ACKNOWLEDGEMENTS Declared none.

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Current Pharmaceutical Design, 2015, Vol. 21, No. 22

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Received: April 9, 2015

Accepted: June 11, 2015

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