[Depression in pregnancy: focus on the safety of antidepressant drugs.] / Depressione in gravidanza: focus sulla sicurezza dei farmaci antidepressivi.

Antepartum depression, frequently in comorbidity with anxiety disorders, is a severe psychopathological condition frequently reported in pregnancy and in many cases associated with obstetric and neonatal complications and potential negative consequences on child neurodevelopment. However, the pharmacological treatment of depression, during pregnancy generates a lot of concerns about the risks of such treatment for the fetus development and the neonatal health. The aim of this review is to present a selection of the latest international literature including recent original studies, systematic reviews, meta-analyses and recommendations from the guidelines, both on the risks of an untreated depressive disorders and on the risk of antidepressant therapy during gestation with drugs belonging to the SSRI and SNRI (SRI) class. An updated information of the recent risk-benefit data of these drug treatments in women with affective disorders in pregnancy may actually enable better and more conscious management of these disorders, not only for those working in the mental health field but also for general practitioners and those of other medical specialties.

Suicide during Perinatal Period: Epidemiology, Risk Factors, and Clinical Correlates.

Perinatal period may pose a great challenge for the clinical management and treatment of psychiatric disorders in women. In fact, several mental illnesses can arise during pregnancy and/or following childbirth. Suicide has been considered a relatively rare event during the perinatal period. However, in some mental disorders (i.e., postpartum depression, bipolar disorder, postpartum psychosis, etc.) have been reported a higher risk of suicidal ideation, suicide attempt, or suicide. Therefore, a complete screening of mothers' mental health should also take into account thoughts of suicide and thoughts about harming infants as well. Clinicians should carefully monitor and early identify related clinical manifestations, potential risk factors, and alarm symptoms related to suicide. The present paper aims at providing a focused review about epidemiological data, risk factors, and an overview about the main clinical correlates associated with the suicidal behavior during the pregnancy and postpartum period. Practical recommendations have been provided as well.

[Aripiprazole in pregnancy: a review of literature]. / Aripiprazolo in gravidanza: una rassegna della letteratura internazionale.

AIM: Data on tolerability and safety of aripiprazolo during pregnancy and in childbirth are so far limited. Aim of the present study is to provide a review of the literature on the safety profile of aripiprazole during pregnancy and on maternal and neonatal outcomes, including two cases coming from our database (www.degradatabase.it). METHODS: Medline database was searched for English language articles by using the following keywords: "aripiprazole", "atypical antipsychotic", "major malformations", "perinatal complications", "pregnancy". We reported 2 cases of women treated with aripiprazole during their pregnancy at the Clinic of Affective Disorders in Pregnancy and Postpartum of the United Hospital of Ancona (DEGRA Center - www.depressionegravidanza.it). RESULTS: The data available in the literature did not provide clear evidence about the safety and potential risks related to this drug during pregnancy. Data coming from our database did not detected any malformations and perinatal complications after exposure to aripiprazole in 2 newborns beyond the first trimester of pregnancy. DISCUSSION AND CONCLUSION: From the evidence available, aripiprazole seems to be an antipsychotic effective and well tolerated in the treatment of women with psychotic disorders in pregnancy. However, further studies are needed to better establish the safety of aripiprazole during pregnancy, particularly as the risk of major malformtions and perinatal complications is concerned.

The safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a comprehensive review.

OBJECTIVE: The present study provides a comprehensive review of the existing literature on the safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and lactation. METHODS: Studies published in English, reporting the use of SNRIs in pregnant and/or breastfeeding women, were identified by searching MEDLINE/Pubmed, PsycINFO, and EMBASE. RESULTS: Twenty-nine studies were included in the review. Altogether, the initial evidence coming from the reviewed studies suggests a lack of association between SNRIs and an increased risk of major congenital malformations. Conversely, exposure to SNRIs seems to be significantly associated with an increased risk of some perinatal complications. No neonatal adverse events emerged, so far, in the few studies concerning the safety of SNRIs during breastfeeding. CONCLUSIONS: Available data suggest that venlafaxine is relatively safe during pregnancy, in particular as far as major malformations are concerned, whereas considering the small number of studies published, no definitive conclusions can be drawn on its safety during breastfeeding. Because of the few studies so far published, the safety of duloxetine during pregnancy and breastfeeding remains to be well established.

Serotonin reuptake inhibitors and breastfeeding: a systematic review.

OBJECTIVE: The postnatal period represents a critical phase for mothers because of physiological hormonal changes, the increase of emotional reactions and a greater susceptibility for the onset/recrudescence of psychiatric disorders. Despite the evidence of an increasing utilization of antidepressant drugs during breastfeeding, there is still few reliable information on the neonatal safety of the selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake inhibitors (SNRIs) [serotonin reuptake inhibitors (SRIs)] in nursing mothers. The aim of this study is to provide a systematic review on the neonatal safety profile of these drugs during breastfeeding, also assessing the limits of available tools. METHODS: MEDLINE and PubMed databases were searched without any language restrictions by using the following set of keywords: ((SSRIs OR selective serotonin inhibitor reuptake OR SNRIs OR selective serotonin noradrenaline inhibitor reuptake) AND (breastfeeding OR lactation OR breast milk)). A separate search was also performed for each SSRIs (paroxetine, fluvoxamine, fluoxetine, sertraline, citalopram and escitalopram) and SNRIs (venlafaxine and duloxetine). RESULTS: Sertraline and paroxetine show a better neonatal safety profile during breastfeeding as compared with other SRIs. Less data are available for fluvoxamine, escitalopram and duloxetine. Few studies followed up infants breastfeed for assessing the neurodevelopmental outcomes. CONCLUSIONS: Literature review clearly indicates paroxetine and sertraline as the drugs that should be preferred as first line choice in nursing women who need an antidepressant treatment.

How much do we know about the coupling of G-proteins to serotonin receptors?

Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several G-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different pathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search was performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public databases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues. Only a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible thousands suggested by expression data analysis have been examined experimentally. In addition this has mostly been obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions have not been explored, our findings suggest additional possible interactions that should be examined based on our expression data analysis.

[Antidepressants-SSRIs in pregnancy and risk of major malformations: treat or not to treat]. / Antidepressivi-SSRI in gravidanza e rischio di malformazioni maggiori: trattare o non trattare?

Considering teratogenic risk, recent data suggest that selective serotonin reuptake inhibitors (SSRIs) can be prescribed during pregnancy, even though some SSRIs are to be considered as a second choice. In any case, antidepressive treatment during pregnancy must be carefully tailored to the pregnant woman, considering absolute risk/benefit ratio of SSRIs, but also availability of other effective treatments, as well as woman's preferences.

Role of 5-HTTLPR polymorphism in the development of the inward/outward personality organization: a genetic association study.

Reciprocity with primary caregivers affects subjects' adaptive abilities toward the construction of the most useful personal meaning organization (PMO) with respect to their developmental environment. Within cognitive theory the post-rationalist approach has outlined two basic categories of identity construction and of regulation of cognitive and emotional processes: the Outward and the Inward PMO. The presence of different, consistent clinical patterns in Inward and Outward subjects is paralleled by differences in cerebral activation during emotional tasks on fMRI and by different expression of some polymorphisms in serotonin pathways. Since several lines of evidence support a role for the 5-HTTLPR polymorphism in mediating individual susceptibility to environmental emotional stimuli, this study was conducted to investigate its influence in the development of the Inward/Outward PMO. PMO was assessed and the 5-HTTLPR polymorphism investigated in 124 healthy subjects who were subdivided into an Inward (n = 52) and an Outward (n = 72) group. Case-control comparisons of short allele (S) frequencies showed significant differences between Inwards and Outwards (p = 0.036, χ2 test; p = 0.026, exact test). Genotype frequencies were not significantly different although values slightly exceeded p ≤ 0.05 (p = 0.056, χ2 test; p = 0.059, exact test). Analysis of the 5-HTTLPR genotypes according to the recessive inheritance model showed that the S/S genotype increased the likelihood of developing an Outward PMO (p = 0.0178, χ2 test; p = 0.0143, exact test; OR = 3.43, CI (95%) = 1.188-9.925). A logistic regression analysis confirmed the association between short allele and S/S genotypes with the Outward PMO also when gender and age were considered. However none of the differences remained significant after correction for multiple testing, even though using the recessive model they approach significance. Overall our data seem to suggest a putative genetic basis for interindividual differences in PMO development.

Safety of escitalopram in pregnancy: a case series.

BACKGROUND: The aim of this paper is to report maternal and neonatal outcomes in pregnant women treated with escitalopram during pregnancy and breastfeeding. METHODS: Women enrolled in the DEGRA Database at the Clinic of Affective Disorders in Pregnancy and Postpartum in Italy, treated during pregnancy with escitalopram and followed up throughout pregnancy, were included in this study. All patients provided written informed consent and the study was approved by the local ethics committee. Psychiatric diagnoses were assessed using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition) Axis I Disorders and symptoms were assessed using the Hamilton Rating Scale for Depression (17 items) and Hamilton Rating Scale for Anxiety (14 items). Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded. RESULTS: The case histories of seven pregnant women treated for depression and/or anxiety disorders with escitalopram were reported. Four women were also treated with benzodiazepines. All pregnancies were full-term and all newborns had normal Apgar scores. There were no major malformations or miscarriages following exposure to escitalopram. Mild withdrawal syndrome was reported only in a newborn who was also exposed to a benzodiazepine. Two infants exposed to escitalopram during breastfeeding did not show any health problems. CONCLUSION: Our experience with use of escitalopram in pregnant women did not reveal any maternal or neonatal concerns. However, considering the few cases analyzed and the paucity of published literature, no conclusions can be drawn on its safety profile in pregnancy and breastfeeding.

Infant health and neurodevelopmental outcomes following prenatal exposure to duloxetine.

Maternal psychiatric disorders can have negative consequences on the fetus and newborn. Thus, the risks of untreated mental disorders in pregnancy should be balanced against the potential risks of a psychopharmacological treatment. The aim of the present report is to provide information on the infant safety of duloxetine exposure, an antidepressant drug belonging to the serotonin-norepinephrine reuptake inhibitors, during pregnancy. Despite duloxetine being routinely prescribed as a treatment for major depression and anxiety disorders, there is a paucity of literature evaluating both the short- and long-term effects of duloxetine exposure in utero. This paper provides data on infant health and neurodevelopmental outcomes, up to 9 months of age, in a newborn exposed to duloxetine throughout pregnancy. Although the present report suggests that duloxetine was not associated with major malformations or neurobehavioural problems, the drug should be used with caution until further information is available on its safety profile in pregnancy.

Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment.

IMPORTANCE: Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects. OBJECTIVE: To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine. DESIGN: In silico predictions, in vitro, and case-control investigations. SETTING: Academic and clinical facilities. PARTICIPANTS: The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks. MAIN OUTCOMES AND MEASURES: In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia. RESULTS: Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment. CONCLUSIONS AND RELEVANCE: Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine.

Psychotropic drug treatment in anorexia nervosa. Search for differences in efficacy/tolerability between adolescent and mixed-age population.

BACKGROUND: During the last 10 years, the use of psychotropic medications in youth with psychiatric disorders, including eating disorders, has significantly increased, but their role in the treatment of adolescent anorexia nervosa is still controversial. OBJECTIVE: This paper aims to review the literature on the use of antidepressants and antipsychotics in adolescents with anorexia nervosa, comparing the efficacy and tolerability in this population with those reported in trials with patients not selected by age. METHOD: A systematic review of the available literature published so far. RESULTS: Only few studies met the selection criteria. No strong evidence of beneficial effects was found in using antidepressants and antipsychotics neither in adults nor in adolescents. Side effects were more frequently reported in studies including adolescent population. Among psychotropic drugs, the majority of studies focused on olanzapine, which seems to have, in some studies, only positive effects on body mass index, eating disorder symptoms and functional impairment in both age groups.

[The safety profile of escitalopram in pregnancy and breastfeeding]. / La sicurezza dell'escitalopram in gravidanza e nell'allattamento.

INTRODUCTION: Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors (SSRI) for the treatment of major depression disorder. However, little is known on its potential risk of inducing major malformations (MM) and/or perinatal complications (PC). Aim of the present study is to provide a review of the available literature on the safety profile of ESC during pregnancy and breastfeeding and to compare data with the maternal and neonatal outcomes of 8 cases of the DEGRA Center. METHODS: MEDLINE and PubMed databases were searched for English language articles by using the following keywords: "escitalopram", "selective serotonin reuptake inhibitors", "major malformations", "perinatal complications", "pregnancy", "breastfeeding". We also reported 8 cases of women treated with ESC during their pregnancy and breastfeeding at the Clinic of Affective Disorders in Pregnancy and Postpartum of the United Hospital of Ancona (DEGRA Center). RESULTS: Although some cases of MM have been reported in the literature after maternal exposure to ESC during early pregnancy, the rate of MM is substantially in the range of those reported in unexposed women. ESC exposure seems to be significantly associated with some PC such as lower rates of live births and higher rates of newborns with low birth weight. On the contrary, no short-term adverse effects in newborns were reported in the 5 studies evaluating the safety of ESC during breastfeeding. Data coming from DEGRA Center are consistent with the literature: all pregnancy were full term, all newborns were healthy and obtained normal APGAR score; no MM or miscarriage were reported. Only one case of mild withdrawal syndrome was reported in a newborn who was also exposed to benzodiazepines and paroxetine late in pregnancy. Two infants exposed to ESC also during the lactation did not reported any adverse effects at short-term. CONCLUSIONS: Data coming from published studies and from our cases seem to support the notion that ESC might be considered safe during pregnancy and breastfeeding, particularly as far as MM is concerned. As well as other SSRI it could be associated with an increased risk of PC. Nevertheless, given the few cases here analysed and the paucity of the studies so far published, no definitive conclusions should be drawn.

Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview.

OBJECTIVE: Benzodiazepines (BDZs) safety profiles in pregnancy suggest that the risk of major malformations (MMs) cannot be considered simply as a "class effect". The aim of this paper was to review and update the available literature on the risks of MMs in women exposed to BDZs in the first trimester of pregnancy. METHODS: PubMed was searched for English-language articles, from January 2001 to November 2011, introducing as keywords "teratogens", " major malformation", "foetus", "infant", "newborn", "pregnancy", in conjunction with "benzodiazepines" as a keyword or BDZ generic name as text words. RESULTS: Twelve studies were selected for the review. BDZ exposure during the first trimester of pregnancy seems not to be associated with an increasing risk of congenital MMs. Diazepam and chlordiazepoxide should be considered drugs of first choice. CONCLUSIONS: Data published in the last 10 years did not indicate an absolute contraindication in prescribing BDZs during the first gestational trimester. In any case, studies analyzed suffer from a number of methodological limitations such as lack of careful report of BDZ patterns of use in pregnancy, possible influences of recall bias, lack of controlling for confounding factors and lack of data concerning possible MMs in aborted fetuses.

Non-monoaminergic targets for the development of antidepressants: focus on neuropeptides.

In the last decades, no significant paradigm shifts in the psychopharmacology of major depressive disorder (MDD) have occurred. In fact, after the serendipitous discovery of the first antidepressant, the poor understanding of the pathophysiology of the illness has deeply limited the development of novel antidepressant agents. Although the discovery of the selective serotonin reuptake inhibitors and the dual-acting serotonin/norepinephrine reuptake inhibitors allowed to improve the treatment of MDD, there are still important unmet clinical needs, as the long latency of antidepressant action, the presence of relevant side effects and the lack of efficacy. In fact, even though the available antidepressants have consistently improved the prognosis of the disorder, the pharmacological treatment of MDD is far from being satisfactory and the disorder remains one of the major causes of morbidity and disability worldwide. Recently, besides the classical research involving the monoamines, other non-monoaminergic molecular mechanisms have been explored in search of new antidepressants. Amongst them, the investigation of the central neuropeptides, including substance P, corticotropin-releasing factor, neuropeptide Y, vasopressin and oxytocin, galanin and melanin-concentrating hormone, is increasingly attracting the attention of researchers worldwide. A number of novel compounds acting on neuropeptide receptors have been developed and tested in both animals and humans with different results. In this review, we provided a synthetic overview of the main neuropeptides, going through biochemical and molecular aspects up to preclinical and clinical evidence which link these molecules to the presence of MDD.

The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review.

OBJECTIVE: Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors for the treatment of major depression. However, little is known on its potential risk of inducing major malformations (MMs) and perinatal complications (PCs). Hence, aim of the present study is to provide a comprehensive review of the available literature on the safety profile of ESC during pregnancy and breastfeeding. METHODS: MEDLINE and PubMed databases were searched for English language articles by using the following keywords: escitalopram, selective serotonin reuptake inhibitors, major malformations, perinatal complications, pregnancy, and breastfeeding. RESULTS: Although some cases of MMs have been reported after maternal exposure to ESC during early pregnancy, the rate of these adverse events is substantially in the range of those reported in unexposed women. On the contrary, exposure to ESC seems to be significantly associated with some PCs. No adverse effects have been reported in the few studies evaluating its safety during breastfeeding. CONCLUSIONS: The available data seem to support the notion that ESC might be considered safe during pregnancy, in particular as far as MMs is concerned. However, similar to other selective serotonin reuptake inhibitors, it could be associated with an increased risk of PCs. Given the paucity of the studies published so far, no definitive conclusions can be drawn on its safety profile during breastfeeding.

Is the cognitive-behavioral therapy an effective intervention to prevent the postnatal depression? A critical review.

OBJECTIVE: The aim of this article is to review and discuss the efficacy of the Cognitive-Behavioral Therapy (CBT), in the prevention of postnatal depression (PD) in pregnant women at risk. METHOD: PubMed, Medline, PsychInfo, Embase, and the Cochrane Library databases were searched from February 1991 to February 2011. RESULTS: Eight Randomized Controlled Trials (RCT) on the prevention of PD with the CBT were selected and their data were analyzed. The literature analyzed recommends that depression in pregnancy requires an efficient management to provide mother's symptoms relief as well as to prevent the PD. While several studies demonstrated the efficacy of the CBT in the treatment of PD, the efficacy of the CBT in preventing PD in pregnant women at risk has been investigated only by a few studies, presenting a number of methodological flaws. CONCLUSIONS: Better designed RCT are needed to support the efficacy of such psychotherapeutic preventive strategy in women at risk for PD.

[Is the cognitive-behavioural therapy an effective strategy also in the prevention of post partum depression? a critical review]. / La terapia cognitivo-comportamentale è una strategia efficace anche nella prevenzione della depressione post partum? Una revisione critica.

OBJECTIVE: The aim of this study was to evaluate the efficacy of cognitive-behavioural therapy (CBT) in the prevention of post partum depression (PPD) in pregnant women at risk. METHODS: PubMed, Medline, PsychInfo, Embase, and the Cochrane Library databases were searched from January 1991 to June 2011 to review studies on the efficacy of CBT in the prevention of PD. RESULTS: The literature analyzed recommends that depression in pregnancy requires an efficient management to provide mother's symptoms relief as well as to prevent PD. While several studies demonstrated the efficacy of CBT in the treatment of PD, only a few controlled studies focused on its efficacy in the prevention of PD in women identified at risk during pregnancy. The efficacy of CBT in preventing PD in pregnant women at risk is supported by only a few studies, presenting some methodological flaws. DISCUSSION: Better designed trials are needed to strongly support the efficacy of such psychotherapeutic preventive strategy in women at risk for PD.

Determinants of ante-partum depression: a multicenter study.

INTRODUCTION: Ante-partum depression (APD) is usually defined as a non-psychotic depressive episode of mild to moderate severity, beginning in or extending into pregnancy. APD has received less attention than postpartum depression. This is a cross-sectional study carried out in the Obstetrics and Gynaecology (OG) departments of four different general hospitals in Italy. METHODS: Women attending consecutively the OG departments for their first ultrasound examination were asked to fill in the Edinburgh Postnatal Depression Scale (EPDS) in its Italian validated version. We used the total scores of the EPDS as a continuous variable for univariate and linear regression analyses; in accordance with the literature, the item analysis of EPDS was carried out by classifying the sample as women with "no depression" (scores 0-9), "possible depression" (scores 10-12), "probable depression" (scores 13+) and "probable APD" (scores 15+). RESULTS: The number of women recruited was 1,608. The EPDS assessment classified 10.9 % of the women as possibly depressed, 8.3 % as probably depressed and 4.7 % probably affected from an APD. EPDS score distribution was associated with nationality (higher scores for foreigners), cohabitation (higher scores for women living with friends or in a community), occupation (higher scores for housewives), past episodes of depression and use of herbal drugs. Non-depressed women had significantly lower values on all ten items as compared with depressed women, however, the pattern of item distribution on the EPDS scale remained similar across depression severity groups. In all four groups item 4 (anxious depression) attained the highest scores, while item 10 (suicidality) attained the lowest scores.

Emerging targets for the pharmacological treatment of depression: focus on melatonergic system.

Depression is a disabling condition which adversely affects a person's family, social and work life, and that is associated with a heavy burden to society. Although the available antidepressants have shown their effectiveness and have greatly improved the prognosis of the disorder, the current management of depression is far from being satisfactory. In the last years, besides the classical research involving serotonin, norepineprine and dopamine, non-monoaminergic mechanisms have been explored in the attempt to discover new antidepressants. One such innovative approach focused on melatonergic system, as melatonin is involved in synchronizing circadian rhythms, which are known to be altered in depression. This narrative review aims to provide a comprehensive overview of different aspects of the melatonergic system, including biochemical and anatomical characteristics, impact on the sleep/wake system, and implications for the treatment of depression. In particular, the observation that melatonin may promote sleep and synchronize the internal clock led to development of high-affinity agonists for melatonin receptors (MT). Agomelatine, a naphthalene bioisostere of melatonin, which combines a potent MT1 and MT2 agonism with 5-HT(2C) receptor antagonism, has been found to be effective in the treatment of depressive and anxiety symptoms associated with major depression, with rapid and beneficial effects on the regulation of sleep continuity and quality. If substantiated by further evidence, the observation that melatonergic system dysfunctions contribute to the development of depression, as well as that the antidepressant action of agomelatine is linked to its binding properties to MT1/MT2 receptors, might open new avenues for the discovery of antidepressive agents.