Publications by authors named "Alfredo Bellon"

17 Publications

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Selective serotonin reuptake inhibitors and risk reduction for cardiovascular disease in patients with schizophrenia: A controversial but promising approach.

World J Psychiatry 2021 Jul 19;11(7):316-324. Epub 2021 Jul 19.

Department of Penn State College of Medicine, Penn State Hershey Medical Center, Hershey, PA 17033, United States.

Patients with schizophrenia (SCZ) are at high risk of cardiovascular disease (CVD) due to an inherited predisposition, a sedentary life style and the use of antipsychotic medications. Several approaches have been taken to minimize this risk but results continue to be unsatisfactory. A potential alternative is prescribing selective serotonin reuptake inhibitors (SSRIs). SSRIs decrease platelet aggregation and reduce the risk of coronary heart disease in patients with depression. We therefore aim to investigate whether there is evidence that supports the use of SSRIs to reduce the risk for CVD in SCZ. A review of the literature revealed five published reports relating to the impact of SSRIs on CV risk in SCZ. Three trials assessed the influence on metabolic parameters of fluvoxamine when combined with clozapine. Two of those studies found improvements with fluvoxamine. Of the other two reports, one indicates SSRIs as a group caused minimal but statistically significant increments in total cholesterol, low-density lipoprotein and triglyceride. The second report suggests that when SSRIs are combined with antipsychotics, the metabolic impact depends on the antipsychotic prescribed. While there are promising results, no conclusions can be made currently on whether SSRIs increase or decrease CV risk in SCZ. Further studies are needed to resolve this matter.
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http://dx.doi.org/10.5498/wjp.v11.i7.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311507PMC
July 2021

Vitamin D regulation of the immune system and its implications for COVID-19: A mini review.

SAGE Open Med 2021 18;9:20503121211014073. Epub 2021 May 18.

Penn State College of Medicine, Penn State University, Milton S. Hershey Medical Center, Hershey, PA, USA.

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is at the origin of the current pandemic, predominantly manifests with severe respiratory symptoms and a heightened immune response. One characteristic of SARS-CoV-2 is its capacity to induce cytokine storm leading to acute respiratory distress syndrome. Consequently, agents with the ability to regulate the immune response, such as vitamin D, could become tools either for the prevention or the attenuation of the most severe consequences of the coronavirus disease 2019 (COVID-19). Vitamin D has shown antimicrobial as well as anti-inflammatory properties. While SARS-CoV-2 promotes the release of proinflammatory cytokines, vitamin D attenuates the release of at least some of these same molecules. Inflammatory cytokines have been associated with the clinical phenomena of COVID-19 and in particular with its most dangerous complications. Therefore, the goals of this article are as follows: first, present the numerous roles vitamin D plays in modulating the immune response; second, gather data currently available on COVID-19 clinical presentation and its relation to cytokines and similar molecules; third, expose what it is known about how coronaviruses elicit an inflammatory reaction; and fourth, discuss the potential contribution of vitamin D in reducing the risk and severity of COVID-19.
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http://dx.doi.org/10.1177/20503121211014073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135207PMC
May 2021

Quetiapine and Wolff-Parkinson-White Syndrome.

Case Rep Psychiatry 2020 11;2020:6633385. Epub 2020 Dec 11.

Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, 500 University Drive P.O. Box 850. Mail Code R130. Hershey, PA 17033-0850, USA.

Quetiapine is occasionally associated with cardiovascular adverse effects such as QTc prolongation. QTc prolongation is a side effect that requires monitoring in order to avoid more serious cardiac complications. One particular understudied area is the potential for antipsychotics to elicit electroconduction abnormalities in patients with Wolff-Parkinson-White (WPW) Syndrome. In the present report, we describe a case of quetiapine overdose in a patient with WPW.
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http://dx.doi.org/10.1155/2020/6633385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748904PMC
December 2020

Clinical and genetic validity of quantitative bipolarity.

Transl Psychiatry 2019 09 16;9(1):228. Epub 2019 Sep 16.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21228, USA.

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.
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http://dx.doi.org/10.1038/s41398-019-0561-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746871PMC
September 2019

Transdifferentiation of Human Circulating Monocytes Into Neuronal-Like Cells in 20 Days and Without Reprograming.

Front Mol Neurosci 2018 19;11:323. Epub 2018 Sep 19.

INSERM U1016, Institut Cochin, Paris, France.

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, = 38,819 cells from 15 donors). To provide context and help researchers decide which model of neuronal development is best suited to address their scientific question,we compared our results with those of other models currently available and exposed advantages and disadvantages of each paradigm.
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http://dx.doi.org/10.3389/fnmol.2018.00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156467PMC
September 2018

Antipsychotics for patients with Wolff-Parkinson-White Syndrome.

Clin Schizophr Relat Psychoses 2019 Jan 3. Epub 2019 Jan 3.

1. Penn State Hershey Medical Center, Department of Psychiatry, Hershey, PA, USA.

Wolff-Parkinson-White syndrome (WPW) is a cardiac conduction abnormality characterized by ventricular contractions that appear sooner than the usual interval regulated by the atrioventricular (AV) node. It is commonly asymptomatic but in rare cases can lead to sudden cardiac death. Little is known about the cardiac effects of antipsychotics on patients with WPW. Here we review all the published information currently available on the use of neuroleptics in patients with this cardiac conduction anomaly. Only a few case reports and one controlled study have been published in this area. The limited existing information suggests patients with WPW may be at higher risk for QTc prolongation when exposed to antipsychotics. It also indicates aripiprazole and droperidol could be potential alternatives but more research on this subject is clearly necessary.
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http://dx.doi.org/10.3371/CSRP.SNCM.121218DOI Listing
January 2019

Reversible Thrombocytopenia after Gabapentin in an HIV-Positive Patient.

Case Rep Psychiatry 2018 4;2018:5927065. Epub 2018 Jan 4.

Department of Psychiatry, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.

Gabapentin has become increasingly used in psychiatric practice specifically for anxiety disorders. Even though gabapentin is not approved by the US Food and Drug Administration to treat anxiety, physicians sometimes use it as an alternative to benzodiazepines in patients with a history of substance abuse. Gabapentin is also prescribed when individuals are at risk of thrombocytopenia which is not considered a side effect. Among patients at risk of thrombocytopenia are those positive for human immunodeficiency virus (HIV). Here we present a case of an HIV-positive man who presented for inpatient psychiatric care with severe anxiety and a history of alcohol and benzodiazepine abuse. In this patient, gabapentin worsened thrombocytopenia after repeated exposure to this medication. We suggest caution when considering gabapentin for patients with preexisting low platelet counts, as there seems to be a risk for worsening thrombocytopenia with this antiepileptic in the presence of HIV infection.
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http://dx.doi.org/10.1155/2018/5927065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817358PMC
January 2018

Associating schizophrenia, long non-coding RNAs and neurostructural dynamics.

Front Mol Neurosci 2015 30;8:57. Epub 2015 Sep 30.

Penn State Hershey Medical Center, Department of Pharmacology Hershey, PA, USA ; Penn State Hershey Medical Center, Department of Psychiatry Hershey, PA, USA.

Several lines of evidence indicate that schizophrenia has a strong genetic component. But the exact nature and functional role of this genetic component in the pathophysiology of this mental illness remains a mystery. Long non-coding RNAs (lncRNAs) are a recently discovered family of molecules that regulate gene transcription through a variety of means. Consequently, lncRNAs could help us bring together apparent unrelated findings in schizophrenia; namely, genomic deficiencies on one side and neuroimaging, as well as postmortem results on the other. In fact, the most consistent finding in schizophrenia is decreased brain size together with enlarged ventricles. This anomaly appears to originate from shorter and less ramified dendrites and axons. But a decrease in neuronal arborizations cannot explain the complex pathophysiology of this psychotic disorder; however, dynamic changes in neuronal structure present throughout life could. It is well recognized that the structure of developing neurons is extremely plastic. This structural plasticity was thought to stop with brain development. However, breakthrough discoveries have shown that neuronal structure retains some degree of plasticity throughout life. What the neuroscientific field is still trying to understand is how these dynamic changes are regulated and lncRNAs represent promising candidates to fill this knowledge gap. Here, we present evidence that associates specific lncRNAs with schizophrenia. We then discuss the potential role of lncRNAs in neurostructural dynamics. Finally, we explain how dynamic neurostructural modifications present throughout life could, in theory, reconcile apparent unrelated findings in schizophrenia.
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http://dx.doi.org/10.3389/fnmol.2015.00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588008PMC
October 2015

Factoring neurotrophins into a neurite-based pathophysiological model of schizophrenia.

Prog Neurobiol 2011 Jun 14;94(1):77-90. Epub 2011 Apr 14.

INSERM U894, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, Paris, France.

Neurotrophins are growth factors that, through variations in concentration and changes in receptor expression, regulate the formation of axons and dendrites during development and throughout adult life. Here we review these growth factors, particularly in the context of schizophrenia, a psychiatric disorder characterized by neurodevelopmental abnormalities. We first discuss emerging information derived from physiologically relevant organotypic cultures and in vivo studies regarding the effects of neurotrophins on the neuronal structure including pruning and GABAergic neurons. We then review postmortem studies of neurotrophin levels and their receptors in brains of individuals with schizophrenia, and compare them with what is known about neurotrophin effects on neuronal structure. This comparison indicates that only some neuropathological defects encountered in patients with schizophrenia can be explained by the single action of neurotrophins on dendrites and axons. However, we propose that a number of inconsistent findings and apparently unrelated results in the schizophrenia field can be reconciled if neurons are considered structurally plastic cells capable of extending and retracting dendrites and axons throughout life.
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http://dx.doi.org/10.1016/j.pneurobio.2011.04.003DOI Listing
June 2011

Association of an UCP4 (SLC25A27) haplotype with ultra-resistant schizophrenia.

Pharmacogenomics 2011 Feb;12(2):185-93

INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, U894 Centre de Psychiatrie et Neurosciences, Paris, France.

Aims: Neuronal uncoupling proteins are involved in the regulation of reactive oxygen species production and intracellular calcium homeostasis, and thus, play a neuroprotective role. In order to explore the potential consequences of neuronal uncoupling proteins variants we examined their association in a sample of Caucasian patients suffering from schizophrenia and phenotyped them according to antipsychotic response.

Materials & Methods: Using a case-control design, we compared the frequencies of 15 genetic variants spanning UCP2, UCP4 and UCP5 in 106 French Caucasian patients suffering from schizophrenia and 127 healthy controls. In addition, patients with schizophrenia who responded to antipsychotic treatment were compared with patients with ultra-resistant schizophrenia (URS). This latter population presented no clinical, social and/or occupational remission despite at least two periods of treatment with conventional or atypical antipsychotic drugs and also with clozapine.

Results: There were no differences in the distribution of the respective alleles between URS and responding patients. However, one haplotype spanning UCP4 was found to be significantly under-represented in URS patients. This relationship remained significant after multiple testing corrections.

Conclusion: Although our sample is of limited size and not representative of schizophrenia as a whole, the association found between the URS group and the UCP4 haplotype is noteworthy as it may influence treatment outcome in schizophrenia.
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http://dx.doi.org/10.2217/pgs.10.179DOI Listing
February 2011

Neuropathological and Reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia.

PLoS One 2010 Apr 22;5(4):e10291. Epub 2010 Apr 22.

INSERM U894, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, Paris, France.

Background: Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.

Principal Findings: Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.

Conclusions: Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010291PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858661PMC
April 2010

One-carbon metabolism and schizophrenia: current challenges and future directions.

Trends Mol Med 2009 Dec 5;15(12):562-70. Epub 2009 Nov 5.

INSERM, Pathophysiology of Psychiatric Disorders, CPN, U894, Sainte-Anne Hospital, Paris F-75014, France.

Schizophrenia is a heterogeneous disease generally considered to result from a combination of heritable and environmental factors. Although its pathophysiology has not been fully determined, biological studies support the involvement of several possible components including altered DNA methylation, abnormal glutamatergic transmission, altered mitochondrial function, folate deficiency and high maternal homocysteine levels. Although these factors have been explored separately, they all involve one-carbon (C1) metabolism. Furthermore, C1 metabolism is well positioned to integrate gene-environment interactions by influencing epigenetic regulation. Here, we discuss the potential roles of C1 metabolism in the pathophysiology of schizophrenia. Understanding the contribution of these mechanisms could yield new therapeutic approaches aiming to counteract disease onset or progression.
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http://dx.doi.org/10.1016/j.molmed.2009.10.001DOI Listing
December 2009

Seizures associated with levofloxacin: case presentation and literature review.

Eur J Clin Pharmacol 2009 Oct 26;65(10):959-62. Epub 2009 Aug 26.

Centre de Psychiatrie et Neurosciences, INSERM U894 Laboratoire de Physiopathologie des Maladies Psychiatriques, Paris, France.

Purpose: We present a case of a patient who developed seizures shortly after initiating treatment with levofloxacin and to discuss the potential drug-drug interactions related to the inhibition of cytochrome P450 (CYP) 1A2 in this case, as well as in other cases, of levofloxacin-induced seizures.

Methods: Several biomedical databases were searched including MEDLINE, Cochrane and Ovid. The main search terms utilized were case report and levofloxacin. The search was limited to studies published in English.

Results: Six cases of levofloxacin-induced seizures have been reported in the literature. Drug-drug interactions related to the inhibition of CYP1A2 by levofloxacin are likely involved in the clinical outcome of these cases.

Conclusions: Clinicians are exhorted to pay close attention when initiating levofloxacin therapy in patients taking medications with epileptogenic properties that are CYP1A2 substrates.
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http://dx.doi.org/10.1007/s00228-009-0717-5DOI Listing
October 2009

Potential application as screening and drug designing tools of cytoarchitectural deficiencies present in three animal models of schizophrenia.

Expert Opin Drug Discov 2009 Mar;4(3):257-78

INSERM, Hôpital Sainte-Anne, Centre de Psychiatrie et Neurosciences, Laboratoire de Physiopathologie des Maladies Psychiatriques, U894, 2 ter rue d'Alésia, 75014 Paris, France +33 1 40788634 ; +33 1 45807293 ;

Background: The development of new treatment alternatives for schizophrenia has been prevented by the unknown etiology of the illness and the divergence of results in the field. However, consistent neuropathological findings are emerging from anatomical areas known to be at the core of schizophrenia. If these deficiencies are replicated in animal models then such anomalies could become the target for a new generation of drugs.

Objective: To determine if the methylazoxymethanol acetate (MAM) model, the heterozygote reeler mouse (HRM) and NMDA-antagonists treated rats replicate neuropathological deficits encountered in patients with schizophrenia and to establish if such changes could lead the search for developing novel treatment alternatives.

Methods: Databases including MEDLINE, Cochrane and Ovid were searched; search terms included neuropathology, schizophrenia and animal models.

Results/conclusions: NMDA-antagonist treated animals partially replicate schizophrenia anomalies in parvalbumin positive interneurons. In contrast, neuroanatomical deficiencies replicated by the MAM model and the HRM in the hippocampus and the prefrontal cortex seem promising targets for future pharmacological research in schizophrenia. Such neuroanatomical findings along with evidence from molecules and genes associated with schizophrenia suggest new drugs should aim to correct deficits in the formation of dendrites and axons that seems to be implicated in this illness pathophysiology.
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http://dx.doi.org/10.1517/17460440902762794DOI Listing
March 2009

Melatonin induces neuritogenesis at early stages in N1E-115 cells through actin rearrangements via activation of protein kinase C and Rho-associated kinase.

J Pineal Res 2007 Apr;42(3):214-21

Instituto Nacional de Psiquiatría, Departamento de Neurofarmacología, Subdirección de Investigaciones Clínicas, Mexico D.F., Mexico.

Melatonin increases neurite formation in N1E-115 cells through microtubule enlargement elicited by calmodulin antagonism and vimentin intermediate filament reorganization caused by protein kinase C (PKC) activation. Microfilament rearrangement is also a necessary process in growth cone formation during neurite outgrowth. In this work, we studied the effect of melatonin on microfilament rearrangements present at early stages of neurite formation and the possible participation of PKC and the Rho-associated kinase (ROCK), which is a downstream kinase in the PKC signaling pathway. The results showed that 1 nm melatonin increased both the number of cells with filopodia and with long neurites. Similar results were obtained with the PKC activator phorbol 12-myristate 13-acetate (PMA). Both melatonin and PMA increased the quantity of filamentous actin. In contrast, the PKC inhibitor bisindolylmaleimide abolished microfilament organization elicited by either melatonin or PMA, while the Rho inhibitor C3, or the ROCK inhibitor Y27632, abolished the bipolar neurite morphology of N1E-115 cells. Instead, these inhibitors prompted neurite ramification. ROCK activity measured in whole cell extracts and in N1E-115 cells was increased in the presence of melatonin and PMA. The results indicate that melatonin increases the number of cells with immature neurites and suggest that these neurites can be susceptible to differentiation by incoming extracellular signals. Data also indicate that PKC and ROCK are involved at initial stages of neurite formation in the mechanism by which melatonin recruits cells for later differentiation.
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http://dx.doi.org/10.1111/j.1600-079X.2006.00408.xDOI Listing
April 2007

Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?

Authors:
Alfredo Bellon

J Psychiatr Pract 2006 Jul;12(4):229-43

Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 6555 Travis, Houston, TX 77030, USA.

Insomnia is one of the most common complaints faced in clinical practice. The limited pharmacological options available make the treatment of this complaint a challenge. All of the available benzodiazepines and non-benzodiazepine hypnotics have the potential to induce addiction, cause withdrawal symptoms, or trigger rebound insomnia. Further, the evidence supporting the utility of commonly prescribed options such as antidepressants and antipsychotics is limited. Melatonin is a hormone that has been associated with soporific effects. Based on this premise, a melatonin receptor agonist was created. Ramelteon was approved by the Food and Drug Administration in 2005 and is the only medication indicated for the long-term treatment of insomnia. A critical review with a clinical perspective of randomized, placebo-controlled clinical trials was conducted to determine the efficacy of melatonin and ramelteon for the treatment of insomnia. Based on this review, it appears that more placebo-controlled trials are indicated before valid judgments concerning the efficacy of both melatonin and ramelteon can be made. In the meantime, there is some support for the use of melatonin for the treatment of insomnia, and findings concerning ramelteon also appear promising. Nevertheless, clinicians who prescribe melatonin or ramelteon should be cautious and carefully monitor both potential benefits and adverse effects, since data on melatonin are based on studies with multiple limitations and only three controlled trials have been done with ramelteon.
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http://dx.doi.org/10.1097/00131746-200607000-00005DOI Listing
July 2006
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