ZWA: Viral genome assembly and characterization hindrances from virus-host chimeric reads; a refining approach.

Viral metagenomics, also known as virome studies, have yielded an unprecedented number of novel sequences, essential in recognizing and characterizing the etiological agent and the origin of emerging infectious diseases. Several tools and pipelines have been developed, to date, for the identification and assembly of viral genomes. Assembly pipelines often result in viral genomes contaminated with host genetic material, some of which are currently deposited into public databases. In the current report, we present a group of deposited sequences that encompass ribosomal RNA (rRNA) contamination. We highlight the detrimental role of chimeric next generation sequencing reads, between host rRNA sequences and viral sequences, in virus genome assembly and we present the hindrances these reads may pose to current methodologies. We have further developed a refining pipeline, the Zero Waste Algorithm (ZWA) that assists in the assembly of low abundance viral genomes. ZWA performs context-depended trimming of chimeric reads, precisely removing their rRNA moiety. These, otherwise discarded, reads were fed to the assembly pipeline and assisted in the construction of larger and cleaner contigs making a substantial impact on current assembly methodologies. ZWA pipeline may significantly enhance virus genome assembly from low abundance samples and virus metagenomics approaches in which a small number of reads determine genome quality and integrity.

A main event and multiple introductions of SARS-CoV-2 initiated the COVID-19 epidemic in Greece.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Chains of infections starting from various countries worldwide seeded the outbreak of COVID-19 in Athens, capital city of Greece. A full-genome analysis of isolates from Athens' hospitals and other healthcare providers revealed the variety of SARS-CoV-2 that initiated the pandemic before lockdown and passenger flight restrictions. A dominant variant, encompassing the G614D amino acid substitution, spread through a major virus dispersal event, and sporadic introductions of rare variants characterized the local initiation of the epidemic. Mutations within the genome highlighted the genetic drift of the virus as rare variants emerged. An important variant contained a premature stop codon in orf7a leading to the truncation of a possibly important for viral pathogenesis domain. This study may serve as a reference for resolving future lines of infection in the area, especially after resumption of passenger flight connections to Athens and Greece during summer of 2020.

Concurrence of anorexia nervosa and Noonan syndrome.

Noonan syndrome (NS) is a genetic disease inherited in an autosomal dominant mode; it presents significant genetic heterogeneity and varying penetrance. Mutations have been identified in several genes, and they account for 75% of all known cases. The majority of reported mutations are localized on PTPN11 gene, which encodes the non-receptor type protein tyrosine phosphatase SHP-2. Diagnosis, however, is mainly established after clinical examination. Anorexia nervosa (AN) is an eating disorder characterized by fear of gaining weight, refusal to maintain normal body weight and distorted perceptions of body image or body shape. AN is independently predicted by female sex and feeding problems in childhood, whereas NS symptoms include feeding difficulties. No comorbidity between NS and AN has been reported to date. The authors reported the case of a 38-year-old female patient with AN who met the van der Burgt criteria for NS with confirmed (a) comorbidity of AN and NS and (b) the absence of the most common mutation in PTPN11 and presence of a novel T > A transversion within intron 8-9.

Defining virus-carrier networks that shape the composition of the mosquito core virome of a local ecosystem.

Mosquitoes are the most important vectors of emerging infectious diseases. During the past decade, our understanding of the diversity of viruses they carry has greatly expanded. Most of these viruses are considered mosquito-specific, but there is increasing evidence that these viruses may affect the vector competence of mosquitoes. Metagenomics approaches have focused on specific mosquito species for the identification of what is called the core virome. Despite the fact that, in most ecosystems, multiple species may participate in virus emergence and circulation, there is a lack of understanding of the virus-carrier/host network for both vector-borne and mosquito-specific viruses. Here, we studied the core virome of mosquitoes in a diverse local ecosystem that had 24 different mosquito species. The analysis of the viromes of these 24 mosquito species resulted in the identification of 34 viruses, which included 15 novel viruses, as determined according to the species demarcation criteria of the respective virus families. Most of the mosquito species had never been analysed previously, and a comparison of the individual viromes of the 24 mosquito species revealed novel relationships among mosquito species and virus families. Groups of related viruses and mosquito species from multiple genera formed a complex web in the local ecosystem. Furthermore, analyses of the virome of mixed-species pools of mosquitoes from representative traps of the local ecosystem showed almost complete overlap with the individual-species viromes identified in the study. Quantitative analysis of viruses' relative abundance revealed a linear relationship to the abundance of the respective carrier/host mosquito species, supporting the theory of a stable core virome in the most abundant species of the local ecosystem. Finally, our study highlights the importance of using a holistic approach to investigating mosquito viromes relationships in rich and diverse ecosystems.

Dissecting the Species-Specific Virome in Culicoides of Thrace.

Biting midges (Culicoides) are vectors of arboviruses of both veterinary and medical importance. The surge of emerging and reemerging vector-borne diseases and their expansion in geographical areas affected by climate change has increased the importance of understanding their capacity to contribute to novel and emerging infectious diseases. The study of Culicoides virome is the first step in the assessment of this potential. In this study, we analyzed the RNA virome of 10 Culicoides species within the geographical area of Thrace in the southeastern part of Europe, a crossing point between Asia and Europe and important path of various arboviruses, utilizing the Ion Torrent next-generation sequencing (NGS) platform and a custom bioinformatics pipeline based on TRINITY assembler and alignment algorithms. The analysis of the RNA virome of 10 Culicoides species resulted in the identification of the genomic signatures of 14 novel RNA viruses, including three fully assembled viruses and four segmented viruses with at least one segment fully assembled, most of which were significantly divergent from previously identified related viruses from the Solemoviridae, Phasmaviridae, Phenuiviridae, Reoviridae, Chuviridae, Partitiviridae, Orthomyxoviridae, Rhabdoviridae, and Flaviviridae families. Each Culicoides species carried a species-specific set of viruses, some of which are related to viruses from other insect vectors in the same area, contributing to the idea of a virus-carrier web within the ecosystem. The identified viruses not only expand our current knowledge on the virome of Culicoides but also set the basis of the genetic diversity of such viruses in the area of southeastern Europe. Furthermore, our study highlights that such metagenomic approaches should include as many species as possible of the local virus-carrier web that interact and share the virome of a geographical area.

Association between vitamin D receptor gene polymorphisms and fibrosis susceptibility in Greek patients with HCV infection.

Introduction: Hepatitis C virus (HCV) infection is a prime cause of chronic hepatitis worldwide, that often silently progresses to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Notably, the majority of individuals infected with HCV develop symptoms at late stages, often associated with liver damage that cannot revert after virus clearance. Thus, current antiviral therapy alone is rather insufficient to eliminate the global burden of HCV in the near future.During the past few years, vitamin D deficiency as well as certain single nucleotide polymorphisms in the vitamin D receptor (VDR) gene have been associated with liver fibrosis. Therefore, the aim of the present study was to investigate the possible correlation between VDR polymorphisms ApaI (rs7975232) and TaqI (rs731236) and the fibrosis stage of patients with HCV infection from Thrace, Greece. Methods: Eighty-one patients with HCV infection underwent transient elastography for the assessment of their fibrosis stage, and PCR-restriction fragment length polymorphism (RFLP) genotyping for VDR ApaI and TaqI polymorphisms. VDR genotypes were then statistically associated with the patients' fibrosis stage using ordinal regression models. Results: Non-cirrhotic stages were positively correlated with TaqI TT genotype (p=0.003) and negatively correlated with TaqI TC genotype (p=0.007). In the presence of Hardy-Weinberg equilibrium and linkage disequilibrium between the two VDR polymorphisms, mild fibrosis stages (F0-2) were correlated with ApaI/TaqI GG/TT (p=0.002) and TG/TT (p=0.008) genotypes, while cirrhotic stage F4 was associated with ApaI/TaqI TG/TC genotype (p=0.038). Conclusions: TaqI TT and ApaI/TaqI GG/TT, TG/TT and TG/TC genotypes could be explored as prognostic genetic markers for fibrosis susceptibility in HCV patients.

The structure of the 5'-untranslated region of mammalian poly(A) polymerase-alpha mRNA suggests a mechanism of translational regulation.

Poly(A)polymerase-alpha (PAPOLA) has been the most extensively investigated mammalian polyadenylating enzyme, mainly in regard to its multifaceted post-translational regulation. The possibility of translational regulation of this enzyme was addressed. The transcription start site was mapped and two uORFs, highly conserved among several species, were identified in the 211-bp long, GC-rich, 5' UTR of the PAPOLA mRNA. Mutation of the 5' proximal AUG resulted in increased translational efficiency of the adjacent coding sequence, whereas no significant effect was observed after mutation of the second AUG. These observations imply that translational regulation is among the conserved mechanisms regulating PAPOLA expression.

Psychological vulnerability differences in students--carriers or not of the serotonin transporter promoter allele S: effect of adverse experiences.

AIM: To study the effect of the serotonin transporting gene L/S polymorphism on several psychological characteristics in a group of Greek University students. METHODS: One hundred eighty-one students were genotyped and classified into two groups: carriers or noncarriers of an S allele. Students were evaluated with a battery of psychological tests (Zung depression rating scale, symptoms check-list-90-R, Eysenck personality inventory); they also answered questionnaires regarding serious past adverse experiences as well as nicotine and alcohol use. Multivariate analysis of variance (MANOVA) was used to check the main effect of genotype and its interaction with both adverse life experiences and scores of psychological tests. RESULTS: No significant differences were detected between the two groups of students regarding scores of the psychological tests. Yet, analysis with MANOVA indicated an interaction between genotype and adversities (lambda = 0.838, F(17,158) = 1.802, P = 0.032). Students who both carry at least one S allele and have faced serious past adverse life experiences have scored higher than carriers of the S allele who have not faced adversities on the following: global severity index (F(1174) = 5.973, P = 0.016), positive symptoms distress index (F(1174) = 4.518, P = 0.035), somatization (F(1174) = 4.074, P = 0.045), depression (F(1174) = 4.971, P = 0.027), anxiety (F(1174) = 8.112, P = 0.005), phobic anxiety (F(1174) = 16.421, P < 0.000), and paranoid ideation (F(1174) = 5.143, P = 0.025). Among students without adversities, those with the LL genotype have scored higher than S allele carriers on the following: depression (t = 2.680, df = 75, P = 0.009), anxiety (t = 2.629, df = 75, P = 0.010), phobic anxiety (t = 3.350, df = 75, P = 0.001), and paranoid ideation (t = 2.668, df = 75, P = 0.009). CONCLUSION: The S and L alleles seem to interact differently with serious past life adversities in influencing psychological vulnerability. Adversities seem to have a stronger effect on S carriers. LL genotype might be related to the expression of certain more endogenous psychopathological tendencies.

Assessment of Gap Junction Protein Beta-2 rs3751385 Gene Polymorphism in Psoriasis Vulgaris.

BACKGROUND: Gap junction protein beta 2 (GJB2) upregulation in psoriasis transcriptome analysis as well as connexin 26 (Cx26, encoded by GJB2) expression upregulation in psoriatic plaques has already been substantiated. GJB2 rs72474224 and rs3751385 have been correlated with psoriasis vulgaris incidence in Chinese populations. Here we study the effect of rs3751385 in patients suffering from psoriasis vulgaris in a Caucasian Greek population at the prefecture of Thrace in Northern Greece. METHODS: One hundred and seventy-three (111 males and 62 females) psoriatic patients (108 were of early-onset psoriasis) and 171 matched controls were included in the study. Genomic DNA was extracted from peripheral blood leukocytes and genotyping was carried out by polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP). RESULTS: A statistically significant lower frequency of C/T genotype in late-onset male psoriasis vulgaris (P = 0.029) as well as of T allele in female early-onset psoriasis vulgaris (P = 0.049) were ascertained. CONCLUSIONS: On condition that all other genetic or environmental factors remain stable, the existence and possible interaction between GJB2 rs3751385 C and T alleles in male psoriatic patients may be considered as protective gene component against late-onset psoriasis appearance, while presence of the T allele in female might block the histogenetic mechanisms of early-onset psoriasis lesions.

Intergenotypic 2k/1b hepatitis C virus recombinants in the East Macedonia and Thrace region of Greece.

BACKGROUND: Intergenotypic recombinant hepatitis C virus (HCV) strains emerge rarely during coinfection of the same individual with two HCV genotypes. Few recombinant HCV strains have been identified to date and only one, CRF01 2k/1b, has become a worldwide concern. This study reevaluated the genotyping of three HCV genotype 2 strains from a group of patients with an unusually low rate of sustained virological response after pegylated interferon/ribavirin treatment. In addition, genetic determinants of host interferon resistance were evaluated. METHODS: The HCV type 2 strains from the patients' serum were subjected to partial sequencing of the core-E1, NS2, NS5A and NS5B regions by reverse transcription polymerase chain reaction. Furthermore, the IFNL3 rs12979860 and the IFNL4 rs368234815 single nucleotide polymorphisms were defined in two of the three patients. RESULTS: All three strains were phylogenetically related to the Russia-derived CRF01 2k/1b while they encompassed the exact same 2k/1b junction site within NS2. CONCLUSION: This is the first report of HCV 2k/1b recombinants in Greece and the greater area of the Balkans.

Relationship between antibodies to hepatitis C virus core+1 protein and treatment outcome.

BACKGROUND: It has been suggested that hepatitis C virus (HCV) core+1 protein plays a crucial role in the viral life cycle, potentially affecting liver cirrhosis and the development of hepatocellular carcinoma. METHODS: To investigate its relationship with the outcome of HCV standard combination therapy with peginterferon-α plus ribavirin, we screened 139 consecutive HCV patients (119 with chronic HCV infection and 20 who spontaneously cleared HCV) for the presence of anti-core+1 antibodies (Abs). In addition, liver fibrosis was determined by FibroScan in all but one patients. RESULTS: Twenty-nine patients were cirrhotic (stiffness >12.5 kPa, F4 METAVIR), all of them with mild liver cirrhosis (Child-Pugh score A). Eighty-six of 139 patients were treatment-experienced with standard combination therapy. Fifty of them had achieved a sustained virological response, while 36 were non-responders. The prevalence of anti-core+1 Abs in patients with chronic HCV infection was 22.69% (27/119 patients): 18% (9/50 patients) in responders and 36.11% (13/36 patients) in non-responders (P=0.050). Five (17.24%) of the 29 cirrhotic patients and 22 (24.72%) of the 89 non-cirrhotic patients were positive for anti-core+1 Abs (P=0.405). Furthermore, the presence of anti-core+1 Abs correlated with the poor response interleukin (IL) 28B genotype TT (P=0.040). No correlation between spontaneous clearance and anti-core+1 Abs was observed (P=0.088). CONCLUSION: The presence of anti-core+1 Abs might be correlated with the poor response IL28B TT genotype and may negatively affect the outcome of standard combination treatments in HCV patients, suggesting that core+1 may play a biological role in the course of HCV infection.

Association of SCN1A gene polymorphism with antiepileptic drug responsiveness in the population of Thrace, Greece.

INTRODUCTION: The aim was to examine the influence of the SCN1A gene polymorphism IVS5-91 rs3812718 G>A on the response to antiepileptic drugs (AEDs) in monotherapy or polytherapy. MATERIAL AND METHODS: Two hundred epilepsy patients and 200 healthy subjects were genotyped for SCN1A IVS5-91 rs3812718 G>A polymorphism using TaqMan assay. Patients were divided into drug-responsive and drug-resistant patients. The drug-responsive group was further studied, comparing monotherapy in maximum and minimum doses and monotherapy-responsive and -resistant groups. RESULTS: There were no statistically significant differences in the allelic frequencies and genotype distributions between patients and controls (p = 0.178). The distribution of SCN1A IVS5-91 rs3812718 G>A genotypes was similar between drug-responsive and drug-resistant patients (p = 0.463). The differences in genotype distributions (A/A or A/G vs. G/G) between monotherapy-responsive and -resistant groups were statistically significant (p = 0.021). Within the monotherapy-responsive group, patients with the A/A or A/G genotype needed higher dose AEDs than patients with the G/G genotype (p = 0.032). The relative risk for generalized epilepsy due to A-containing genotypes was of marginal statistical significance when compared with the G/G genotype (p = 0.05). CONCLUSIONS: Overall, our findings demonstrate an association of SCN1A IVS5-91 rs3812718 G>A polymorphism with AED responsiveness in monotherapy without evidence of an effect on drug-resistant epilepsy.

Assessment of Tachykinin Receptor 3' Gene Polymorphism rs3733631 in Rosacea.

Background. Rosacea is a chronic skin disease, possibly following the neurogenic skin inflammation model. Neurokinin B, involved in the pathogenesis of Parkinson's disease, frequently coexisting with subsequent onset of rosacea, is an endogenous ligand of the tachykinin receptor 3 (TACR3). Methods. 128 rosacea patients and 121 matched controls were genotyped for rs3733631 by PCR-RFLP and analyzed by chi-square test. Results. We observed statistically significant predominance of the C/G or G/G genotype (p = 0.006) and of the G allele (p = 0.004) in the papulopustular (PP) form of rosacea and statistically marginal significance of the C/G or G/G genotype in erythematotelangiectatic (ET) rosacea (p = 0.052). Significantly higher frequency of the C/G or G/G genotype and G allele in PP rosacea (p = 0.021 and p = 0.008, resp.) was ascertained within male patients. Conclusion. TACR3 rs3733631 G allele possibly predisposes the evolution of the initial phase of rosacea to the PP and not the ET form in male patients.

Assessment of Leptin Gene Polymorphism rs2060713 in Psoriasis Vulgaris.

Psoriasis is a lifelong disorder characterized by approximately 8-fold reduction of the duration of normal skin keratinocyte cell cycle and 2-fold increase of the number of dividing cells. Multiple genes, several environmental factors, and immune system alterations are involved in the pathogenesis of psoriasis. Hyperleptinemia is associated with psoriasis and leptin acts as an angiogenic factor. Angiogenetic processes precede the epidermal hyperplasia in psoriasis, indicating possible involvement of leptin in the pathogenesis of psoriasis. Leptin gene polymorphisms and their association with psoriasis have been given very little attention. We present a study of the rs2060713C/T genetic polymorphism in the pathogenesis of psoriasis vulgaris in 263 vulgaris patients and 252 unrelated matched healthy controls. No statistically significant differences were observed between patients and controls. A statistically nonsignificant trend was observed in males with the early onset type of psoriasis (11.1% C/T in patients versus 5.6% in controls) and in females with the late onset type of the disease (12.8% C/T in patients versus 3.3% in controls). Still, there is no hard evidence on correlation of psoriasis vulgaris with this polymorphism. Possible association with specific forms of the disease and either gender needs further investigation in larger studies.

notch2, notch4 gene polymorphisms in psoriasis vulgaris.

BACKGROUND: Evidence suggests that Notch gene aberrations may be involved in the clinical expression of psoriasis. There are reports of Notch2 receptor expression peculiarities in psoriatic skin and others, indicating that VEGF-induced Notch4 overexpression promotes endothelial cell morphology alterations and that increased dermis vessel permeability histogenetically precedes the development of psoriatic lesions. OBJECTIVE: To investigate the correlation of polymorphisms in Notch2 and Notch4 genes with the appearance of psoriasis vulgaris. MATERIAL AND METHODS: Up to 305 patients suffering from psoriasis vulgaris were included in the study, genotyped by either real time quantitative PCR or PCR-RFLP. RESULTS: We observed: (a) Notch2: Statistically significant predominance of T/C genotype in male patients (p=0.037); (b) Notch4: Significantly higher frequency of the SNP1 T/T genotype (p=0.039) in psoriatic females; significant predominance of the SNP2 G/G and A/G (p=0.014) genotypes in female patients with late onset psoriasis (p=0.001). CONCLUSION: This study supports the involvement of both Notch2 and Notch4 in the pathogenesis of psoriasis vulgaris. Pathogenetic participation of Notch2 seems more evident in male patients, possibly early onset, while that of Notch4 is more evident in late onset female patients.

Effect of BDNF Val66Met and serotonin transporter 5-HTTLPR polymorphisms on psychopathological characteristics in a sample of university students.

OBJECTIVE: The aims of this study were to evaluate the impact of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on several psychological characteristics in a group of Greek University students and to explore putative interactions with the serotonin-transporter-linked polymorphic region (5-HTTLPR) and serious past adverse experiences. METHODS: A total of 224 students were genotyped and classified as (a) carriers or noncarriers of the Met allele of the BDNF Val66Met polymorphism and (b) carriers or noncarriers of the S or Lg alleles (S') of the 5-HTTLPR polymorphism. Students were evaluated using a battery of standard psychological tests and answered questionnaires on serious past adverse experiences. RESULTS: The Val/Val BDNF genotype was associated with higher scores in several psychopathological dimensions. When the effect of the BDNF Met allele was examined in relation to 5-HTTLPR, it was restricted to S' noncarriers. Among these students, BDNF Met allele carriers had lower scores compared with noncarriers. The effects of the Met allele on the S' allele noncarriers in the anxiety and phobic anxiety dimensions were more pronounced among individuals who had reported no serious life adversities. CONCLUSION: There may be a protective role of the BDNF Met allele in several psychopathological features and it is suggested that some of these effects are moderated by 5-HTTLPR.

Assessment of insertion/deletion polymorphism of the angiotensin-converting enzyme gene in abdominal aortic aneurysm and inguinal hernia.

The aim of the paper is to determine whether the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with abdominal aortic aneurysm (AAA) and inguinal hernia. A case-control study was conducted in 264 subjects: 65 patients with AAA, 91 patients with inguinal hernia, 19 patients with both AAA and hernia, and 89 controls were investigated for the ACE I/D polymorphism. Genotype analysis was performed using a polymerase chain reaction technique. Significant differences in the genotype between the patient groups and controls were identified (aneurysm versus control, P = 0.011; aneurysm plus hernia versus control, P = 0.022; hernia versus control, P = 0.001), whereas no differences were found within patient groups. Patients with AAA and/or hernia had an increased prevalence of I/D heterozygosity, which persisted even after adjusting for differences in confounding clinical variables (aneurysm versus control, OR 0.3, 95% CI 0.2-0.8, P = 0.005; aneurysm plus hernia versus control, OR 0.3, 95% CI 0.1-0.9, P = 0.040; hernia versus control, OR 0.4, 95% CI 0.2-0.7, P = 0.004). In conclusion, an association between the heterozygote ACE I/D state and the presence of AAA and/or hernia was identified. The role of the ACE I/D polymorphism in aneurysm and hernia needs further investigation.

APOE gene polymorphisms and diabetic peripheral neuropathy.

Genetic factors may influence the natural course of diabetic peripheral neuropathy and explain some of its variability. The aim of this review was to examine the association between apolipoprotein E (apoE) gene polymorphisms and diabetic peripheral neuropathy. Four relevant studies were identified. The two earlier works provided evidence that the ɛ4 allele is a risk factor for this complication, while the two more recent studies were negative. Important differences in the methodology used and in the populations included are obvious, rendering difficult the comparison between studies. In conclusion, the association between APOE gene polymorphisms and diabetic peripheral neuropathy is still unclear. Available evidence is rather limited and results have so far been contradictory. Future studies should employ more robust methodology, adjusting for potential confounders and for the prevalence of neuropathy in the general population with diabetes.

Neuropeptide and sigma receptors as novel therapeutic targets for the pharmacotherapy of depression.

Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.