neuropeptide-y and Depressive-Disorder--Major

Obesity and mood disorders are often overlapping pathologies that are prevalent public health concerns. Many studies have indicated a positive correlation between depression and obesity, although weight loss and decreased appetite are also recognized as features of depression. Accordingly, DSM-5 defines two subtypes of depression associated with changes in feeding: melancholic depression, characterized by anhedonia and associated with decreased feeding and appetite; and atypical depression, characterized by fatigue, sleepiness, hyperphagia, and weight gain. The central nervous system plays a key role in the regulation of feeding and mood, thus suggesting that overlapping neuronal circuits may be involved in their modulation. However, these circuits have yet to be completely characterized. The central melanocortin system, a circuitry characterized by the expression of specific peptides (pro-opiomelanocortins, agouti-related protein, and neuropeptide Y) and their melanocortin receptors, has been shown to be a key player in the regulation of feeding. In addition, the melanocortin system has also been shown to affect anxiety and depressive-like behavior, thus suggesting a possible role of the melanocortin system as a biological substrate linking feeding and depression. However, more studies are needed to fully understand this complex system and its role in regulating metabolic and mood disorders. In this review, we will discuss the current literature on the role of the melanocortin system in human and animal models in feeding and mood regulation, providing evidence of the biological interplay between anxiety, major depressive disorders, appetite, and body weight regulation.

Topics: Animals; Depressive Disorder, Major; Energy Metabolism; Melanocortins; Mood Disorders; Neuropeptide Y; Obesity

Resilience is the ability to cope with critical situations through the use of personal and socially mediated resources. Since a lack of resilience increases the risk of developing stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), a better understanding of the biological background is of great value to provide better prevention and treatment options. Resilience is undeniably influenced by genetic factors, but very little is known about the exact underlying mechanisms. A recently published genome-wide association study (GWAS) on resilience has identified three new susceptibility loci, DCLK2, KLHL36, and SLC15A5. Further interesting results can be found in association analyses of gene variants of the stress response system, which is closely related to resilience, and PTSD and MDD. Several promising genes, such as the COMT (catechol-O-methyltransferase) gene, the serotonin transporter gene (SLC6A4), and neuropeptide Y (NPY) suggest gene × environment interaction between genetic variants, childhood adversity, and the occurrence of PTSD and MDD, indicating an impact of these genes on resilience. GWAS on PTSD and MDD provide another approach to identifying new disease-associated loci and, although the functional significance for disease development for most of these risk genes is still unknown, they are potential candidates due to the overlap of stress-related psychiatric disorders and resilience. In the future, it will be important for genetic studies to focus more on resilience than on pathological phenotypes, to develop reasonable concepts for measuring resilience, and to establish international cooperations to generate sufficiently large samples.

Topics: Adaptation, Psychological; Catechol O-Methyltransferase; Depression; Depressive Disorder, Major; Gene-Environment Interaction; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Neuropeptide Y; Resilience, Psychological; Serotonin Plasma Membrane Transport Proteins; Stress Disorders, Post-Traumatic; Stress, Psychological

Previous studies have suggested that neuropeptide Y (NPY) levels may be altered in patients with major depressive disorder (MDD), post-traumatic stress disorder (PTSD) and chronic stress. We investigated, through systematic review and meta-analysis, whether the mean levels of NPY are significantly different in patients with MDD, PTSD or chronic stress, compared to controls. The main outcome was the pooled standardized mean difference (SMD) with 95% confidence intervals between cases and controls, using the random-effects model. Heterogeneity and publication bias were evaluated. Thirty-five studies met eligibility criteria. Meta-regression determined that medication and sex could explain 27% of the between-study variance. Females and participants currently prescribed psychotropic medications had significantly higher levels of NPY. NPY levels were significantly lower in plasma and cerebrospinal fluid (CSF) in PTSD patients versus controls. Patients with MDD had significantly lower levels of NPY in plasma compared to controls, but not in the CSF. The magnitudes of the decrease in plasma NPY levels were not significantly different between PTSD and MDD. However, chronic stress patients had significantly higher plasma NPY levels compared to controls, PTSD or MDD. Our findings may imply a shared role of NPY in trauma and depression: nevertheless, it is not clear that the association is specific to these disorders. Psychotropic medications may help restore NPY levels. Further controlled studies are needed to better delineate the contribution of confounding variables such as type of depression, body mass index, appetite or sleep architecture.

Topics: Depressive Disorder, Major; Humans; Neuropeptide Y; Stress Disorders, Post-Traumatic; Stress, Psychological

Since about one-third of patients with major depressive disorder (MDD) do not respond adequately to available antidepressants, there is a need for treatments based on novel mechanisms of action. Neuropeptide Y (NPY), a normal brain constituent, is reduced in cerebrospinal fluid of patients with MDD and post-traumatic stress disorder and in corresponding rodent models. Moreover, NPY administered centrally or intranasally rescues pathophysiology in these models. Consequently, we conducted the first, to our knowledge, controlled trial of NPY as a treatment for MDD.. Thirty MDD patients on a stable dose of a conventional antidepressant insufflated 6.8 mg NPY (n = 12) or placebo (n = 18) in a double blind randomized fashion. Effects were assessed at baseline, +1 hour, +5 hours, +24 hours, and +48 hours. The primary outcome was change in depression severity measured with the Montgomery-Åsberg Depression Rating Scale (MADRS).. NPY was superior to placebo at +24 hours (change -10.3 [95% CI: -13.8; -6.8]) vs -5.6 (95% CI: -8.4; -2.7); group*time F = 3.26, DF = (1,28), P = .04; Cohen's d = 0.67). At +5 hours MADRS decreased -7.1 ([95% CI: -10.0; -4.2] vs -3.5 [95% CI: -5.8; -1.2]; group*time F = 2.69, DF = (1,28), P = .05; Cohen's d = 0.61). MADRS reduction at +48 hours was not significant.. Since no results regarding the trajectory of NPY effects existed prior to this study we extrapolated from the known NPY biology and predicted the effects will occur 5-48 hours post insufflation. We chose +48 hours as the primary endpoint and +1, +5, and +24 hours as secondary endpoints. The results, the first of their kind, indicate that insufflated NPY is antidepressant, despite not meeting the primary outcome, and call for dose ranging and repeated NPY insufflation trials.. EudraCT Number: 2014-000129-19.

Topics: Administration, Intranasal; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropeptide Y; Outcome Assessment, Health Care; Severity of Illness Index

The purpose of this study was to examine the differential effects of acute tryptophan (TRP) depletion vs. sham condition on plasma, cerebrospinal fluid (CSF) biochemical parameters, and mood in the following three subject groups: (1) nine antidepressant-free individuals with remitted depression, (2) eight paroxetine-treated individuals with recently remitted depression, and (3) seven healthy controls. Plasma TRP decreased during TRP depletion and increased during sham condition (p<.01). CSF TRP and 5-hydroxyindoleacetic acid were lower during TRP depletion than sham condition (p<.01 each). During TRP depletion, CSF TRP correlated significantly with the plasma sum of large neutral amino acids (SigmaLNAA) (R=-.52, p=.01), but did not significantly correlate with plasma TRP (R=.15, p=.52). The correlation between CSF TRP and ratio of TRP to SigmaLNAA was R=.41 and p=.06 during TRP depletion, and R=-.44 and p=.04 during sham condition. A negative correlation trend was observed between CSF-TRP levels and peak Hamilton Depression Rating Scale scores during TRP depletion in patients recovered from depression (R=-.45, p=.07), but not in healthy controls (R=-.01, p=.98). CSF neuropeptide Y was higher during TRP depletion than sham condition (t=1.75, p<.10). These results illustrate the importance of assessing plasma SigmaLNAA when using the TRP depletion paradigm. The use of a single CSF sampling technique although practical may result in data acquisition limitations.

Topics: Adult; Analysis of Variance; Case-Control Studies; Chromatography, High Pressure Liquid; Circadian Rhythm; Cross-Over Studies; Depressive Disorder, Major; Double-Blind Method; Electrochemistry; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Indoles; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurochemistry; Neuropeptide Y; Paroxetine; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Tryptophan; Young Adult

Major depressive disorder (MDD) is inconsistently associated with elevations in proinflammatory cytokines and neuropeptides. We used a skin sweat patch, recently validated in healthy control subjects, and recycling immunoaffinity chromatography to measure neuroimmune biomarkers in patients with MDD mostly in remission.. We collected blood at 8:00 am and applied skin sweat patches for 24 hours in 21- to 45-year-old premenopausal women (n = 19) with MDD (17/19 in remission) and age-matched healthy controls (n = 17) participating in the POWER (Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression) Study.. Proinflammatory cytokines, neuropeptide Y, substance P, and calcitonin-gene-related peptide were significantly higher and vasoactive intestinal peptide, a marker of parasympathetic activity, was significantly lower in patients compared to controls, and depressive symptomatology strongly correlated with biomarker levels. All analytes were strongly correlated in the skin sweat patch and plasma in patients (r = .73 to .99; p < .0004).. The skin sweat patch allows detection of disrupted patterns of proinflammatory cytokines and neuropeptides in women with MDD in clinical remission, which could predispose to medical consequences such as cardiovascular disease, osteoporosis, and diabetes. This method permits measurement of cytokines in ambulatory settings where blood collection is not feasible.

Topics: Adult; Biomarkers; Calcitonin Gene-Related Peptide; Case-Control Studies; Catecholamines; Chromatography, Affinity; Cytokines; Depressive Disorder, Major; Female; Humans; Hydrocortisone; Longitudinal Studies; Neuropeptide Y; Premenopause; Substance P; Sweat; Young Adult

Neuropeptide Y (NPY) and serotonergic systems have been implicated in the pathophysiology of depression but have not yet been linked together.. In a randomized, double-blind crossover study, 28 medication-free patients with remitted depression and 26 healthy control subjects underwent tryptophan depletion (TD) and sham depletion. Plasma NPY concentrations were determined at baseline and at +5, +7, and +24 h during TD and sham depletion, respectively. Hamilton Depression Rating Scale (HDRS, 24-item) scores were assessed at baseline and at +7 and +24 h after TD and sham depletion, respectively.. There was no difference between healthy subjects and patients with remitted depression in baseline plasma NPY concentrations and in plasma NPY concentrations during TD and sham depletion, respectively. Plasma NPY concentrations did not differ between TD and sham depletion. At no time point there was an association between HDRS scores and plasma NPY concentrations in patients with remitted depression.. Plasma NPY concentrations in rMDD patients were not obtained during the symptomatic phase of the illness. Only peripheral measurements of NPY were used.. Decreased plasma NPY concentrations, as described previously during a spontaneous episode of major depression, appear as state but not as trait marker in depression. No evidence was found for an involvement of plasma NPY in relapse during TD. There appears no direct functional link between serotonergic neurotransmission and plasma NPY concentrations.

Topics: Adult; Cross-Over Studies; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Male; Neuropeptide Y; Remission Induction; Serotonin; Surveys and Questionnaires; Tryptophan; Young Adult

Preclinical and clinical studies suggest that neuropeptide Y (NPY) exerts functional corticotropin-releasing hormone (CRH) antagonistic effects. NPY activity appears to be blunted in depression. Recently, we have found in young normal male controls after repetitive administration of NPY a shortened sleep latency and a decrease of time awake and, in the second half of the night, EEG delta-power; cortisol and ACTH levels were blunted. Since during depression there is an overactivity of CRH, we tested the capacity of NPY to affect sleep endocrine activity in patients with depression compared with controls. After one night of adaptation we administered hourly IV injections of placebo (PL) during the second night and of 50 microg NPY during the third night between 22:00 and 01:00 h. Throughout the night ACTH, cortisol and prolactin levels were measured, simultaneously the sleep electroencephalogram (EEG) was recorded. Depressed patients as well as healthy controls exhibited significant shortening of sleep onset latency (SOL) (mean+/-SD; controls: 41.9+/-48.2 min PL vs 22.1+/-17.3 min NPY; patients: 31.8+/-19.8 min PL vs 24.7+/-20.1 min NPY; P<0.06) and REM latency (controls: 79.3+/-27.5 min PL vs 69.0+/-19.4 min NPY; patients: 79.8+/-45.5 min PL vs 52.4+/-51.2 min NPY; P<0.05). Both patients and controls showed a trend to an increase of prolactin during the night. In contrast to our recent observation in young normal subjects time awake, ACTH and cortisol remained unchanged in patients and controls in response to NPY. Whereas also an adaptation effect may contribute to the shortening of SOL, this change and the prolactin elevation are in line with a CRH antagonistic and GABA(A) agonistic/benzodiazepine-like effect of NPY. The lack of effects on time awake and HPA hormones may be explained by the higher CRH activity due to age and depression in the investigated samples in comparison to our recent study in young subjects.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Depressive Disorder, Major; Electroencephalography; Female; Humans; Hydrocortisone; Male; Middle Aged; Neuropeptide Y; Prolactin; Psychiatric Status Rating Scales; Sleep

Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID-19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain-derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R-GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R-GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant-like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive-affecting diseases.

Topics: Administration, Intranasal; Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; COVID-19; Depressive Disorder, Major; Gonadal Steroid Hormones; Hippocampus; Male; Neurogenesis; Neuropeptide Y; Pandemics; Rats; Receptor, Galanin, Type 2; Receptors, Neuropeptide Y

Different brain regions' interactions have been implicated in relevant neurological diseases, such as major depressive disorder (MDD), anxiety disorders, age-dependent cognitive decline, Alzheimer's disease (AD) and addiction. We aim to explore the role of the medial prefrontal cortex (mPFC) in the Neuropeptide Y (NPY) and Galanin (GAL) interaction since we have demonstrated specific NPY and GAL interactions in brain areas related to these brain diseases. We performed GALR2 and Y1R agonists intranasal infusion and analyzed the mPFC activation through c-Fos expression. To assess the associated cellular mechanism we studied the formation of Y1R-GALR2 heteroreceptor complexes with in situ proximity ligation assay (PLA) and the expression of the brain-derived neurotrophic factor (BDNF). Moreover, the functional outcome of the NPY and GAL interaction on the mPFC was evaluated in the novel object preference task. We demonstrated that the intranasal administration of both agonists decrease the medial prefrontal cortex activation as shown with the c-Fos expression. These effects were mediated by the decreased formation of Y1R-GALR2 heteroreceptor complexes without affecting the BDNF expression. The functional outcome of this interaction was related to an impaired performance on the novel object preference task. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the medial prefrontal cortex for the novel therapy on neurodegenerative and psychiatric diseases. DATA SHARING AND DATA ACCESSIBILITY: The data that support the findings of this study are openly available in Institutional repository of the University of Malaga (RIUMA) and from the corresponding author upon reasonable request.

Topics: Administration, Intranasal; Animals; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Humans; Neuropeptide Y; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Task Performance and Analysis

Stress increases the risk for major depressive disorder (MDD), overeating, and alcohol dependence (AD). The neuropeptide Y system is one of the best-known modulators of the stress response, and some of its effects are mediated through the neuropeptide Y receptor Y2 (NPY2R). The functional NPY2R variant rs6857715 (C-599T) has been implicated in both obesity and AD, but with opposing alleles. The present study explored whether rs6857715 is also associated with MDD. Analysis of the overall sample (595 MDD cases; 1295 controls) showed an association with the AD risk allele C [P=0.020, odds ratio (OR) (C-allele)=1.18]. The association remained significant after excluding MDD patients with AD/alcohol abuse [P=0.038, OR (C-allele)=1.18]; increased weight/appetite [P=0.006, OR (C-allele)=1.23]; or both [P=0.008, OR (C-allele)=1.25]. The present findings suggest that the NPY2R rs6857715 C-allele makes a genuine contribution toward MDD.

Topics: Adult; Alcoholism; Alleles; Case-Control Studies; Depressive Disorder, Major; Female; Genetic Predisposition to Disease; Germany; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Odds Ratio; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Neuropeptide Y

Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants.. In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY-like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers.. Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group (p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma (p = 0.001) may be indicative of an intact but insufficient NPY-related stress response.. We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences.

Topics: Adolescent; Adult; Aged; Child; Child Abuse; Depressive Disorder, Major; Humans; Middle Aged; Neuropeptide Y; Spinal Puncture; Young Adult

This study aimed to investigate the single nucleotide polymorphisms (SNPs) of neuropeptide Y (NPY) and major depressive disorder (MDD) in Chinese Han population.. Prospective and randomized studies were carried out.. A total of 700 patients (324 male and 376 female; mean age = 40±14.9 years) with depression who met the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and 673 healthy controls (313 male and 360 female; mean age = 41.9±17.2 years) were used to investigate the relationship between SNPs of NPY and the pathogenesis of MDD. A total of 417 patients (195 male and 202 female; mean age = 36±14.2 years) diagnosed with MDD and 314 healthy controls (153 male and 161 female; mean age = 37.9±14.2 years) from Chinese Han population were used to verify the relationship between SNPs of NPY and the pathogenesis of MDD.. Ligase detection reactions were performed to detect the SNP sites of NPY. A series of statistical methods was carried out to investigate the correlation between the NPY gene SNP and MDD.. Statistical analysis showed a significant correlation between the SNP sites rs16139 in NPY and the morbidity of depression. Patients with MDD have a lower frequency of A-allele in rs16139 in replicate samples from Chinese Han population. However, the frequency varied between male and female patients.. The gene polymorphism loci rs16139 was closely related to MDD in Chinese Han population.

Topics: Adult; Alleles; Asian People; Case-Control Studies; China; Depressive Disorder, Major; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Linkage Disequilibrium; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide

A number of studies have shown that elevated levels of inflammatory cytokines may promote depression and suicidal ideation and that neuroprotective peptides may decrease the response to stress and depression. In this study, cerebrospinal fluid (CSF) levels of three inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor α (TNFα)) and two putative "resiliency" neuropeptides (brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY)) were compared between patients with depression and healthy controls.. Eighteen patients with major depression and 25 healthy controls underwent a lumbar puncture; CSF samples were withdrawn and assayed for IL-1, IL-6, TNFα, BDNF, and NPY levels. Patients with depression were then entered into an 8-week treatment protocol and had repeated lumbar puncture procedures post-treatment.. Contrary to prediction, we found that at baseline depressed patients had higher CSF NPY concentration compared to the normal comparison group. Within the depressed patients, we found several statistically significant correlations between elevated CSF cytokine levels and clinical severity.. Despite the small sample size, given the challenges in obtaining CSF from patients with depression these data are of interest in confirming some aspects of the inflammatory hypothesis of depression.

Topics: Adult; Antidepressive Agents, Second-Generation; Brain-Derived Neurotrophic Factor; Cyclohexanols; Depressive Disorder, Major; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-6; Male; Middle Aged; Neuropeptide Y; Severity of Illness Index; Tumor Necrosis Factor-alpha; Up-Regulation; Venlafaxine Hydrochloride

Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n=21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuron-related peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.

Topics: Adolescent; Adult; Aged; Amygdala; Animals; Brain-Derived Neurotrophic Factor; Case-Control Studies; Depressive Disorder, Major; Down-Regulation; Female; GABAergic Neurons; Gene Expression Profiling; Genetic Association Studies; Humans; Mice; Mice, Knockout; Middle Aged; Neuropeptide Y; Neuropeptides; Somatostatin; Tachykinins

Depression and eating disorders are frequently associated, but the molecular pathways responsible for co-occurrence of altered mood, appetite and body weight are not yet fully understood. Neuropeptide Y (NPY) has potent antidepressant and orexigenic properties and low central NPY levels have been reported in major depression. In the present study, we hypothesized that in patients with major depression alteration of mood, appetite and body weight may be related to NPY-reactive autoantibodies (autoAbs). To test this hypothesis, we compared plasma levels and affinities of NPY-reactive autoAbs between patients with major depression and healthy controls. Then, to evaluate if changes of NPY autoAb properties can be causally related to altered mood and appetite, we developed central and peripheral passive transfer models of human autoAbs in mice and studied depressive-like behavior in forced-swim test and food intake. We found that plasma levels of NPY IgG autoAbs were lower in patients with moderate but not with mild depression correlating negatively with the Montgomery-Åsberg Depression Rating Scale scores and with immobility time of the forced-swim test in mice after peripheral injection of autoAbs. No significant differences in NPY IgG autoAb affinities between patients with depression and controls were found, but higher affinity of IgG autoAbs for NPY was associated with lower body mass index and prevented NPY-induced orexigenic response in mice after their central injection. These data suggest that changes of plasma levels of anti-NPY autoAbs are relevant to altered mood, while changes of their affinity may participate in altered appetite and body weight in patients with depressive disorder.

Topics: Adult; Affect; Amygdala; Animals; Appetite; Autoantibodies; Depressive Disorder, Major; Eating; Humans; Hypothalamus; Immunoglobulin G; Male; Mice; Middle Aged; Neuropeptide Y; Pro-Opiomelanocortin; Swimming

Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P=0.038; odds ratio (OR) AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P=0.034; OR C allele=0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95% CI 1.13-1.63; P=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P=0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

Topics: Computational Biology; Depressive Disorder, Major; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Linkage Disequilibrium; Nerve Tissue Proteins; Neuropeptide Y; Norepinephrine Plasma Membrane Transport Proteins; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; PubMed; Tumor Necrosis Factor-alpha

Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD).. To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis.. Cross-sectional, case-control study.. Academic medical center.. Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data.. Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD.. Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results.. These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.

Topics: Adult; Amygdala; Arousal; Brain; Brain Mapping; Case-Control Studies; Cross-Sectional Studies; Depressive Disorder, Major; Emotions; Female; Gene Expression; Genetic Predisposition to Disease; Genetic Variation; Genotype; Gyrus Cinguli; Haplotypes; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Neuropeptide Y; Pain; Phenotype; Polymorphism, Single Nucleotide; Prefrontal Cortex; Reference Values; Young Adult

Serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) have been the putative markers of MDD. Neuropeptide Y (NPY) may have an important role in the pathophysiology of major depressive disorder (MDD). However, direct measures of cerebrospinal fluid (CSF) 5-HT and NPY in severe MDD have been lacking. In the present study, we examined CSF 5-HT, 5-HIAA and NPY levels and correlate them with gender and suicidal behavior of severe major depressive disorder. Forty drug-free subjects with a severe major depressive disorder and forty control subjects underwent lumber puncture and psychiatric evaluation. Cerebrospinal fluid levels of 5-HT, 5-HIAA and NPY were assayed by enzyme-linked immunosorbent assay (ELISA) test. The relationships among 5-HT, 5-HIAA, NPY and clinical variables were statistically evaluated. There were no differences between severe major depressive disorder and controls in all parameters measured. In severe MDD group, significantly lower CSF 5-HT and higher 5-HT turnover (5-HIAA/5-HT) were found in female patients compared with male patients. The patients with intense suicidal intents and suicidal attempts had significantly lower CSF 5-HT compared to patients with nonsuicidal intents. Additionally, significantly lower CSF NPY was found in first episode depressed patients compared with recurrent depressed patients. Gender-related difference in CSF 5-HT implied a female preponderance in major depression to some extent. Cerebrospinal fluid 5-HT levels and 5-HT turnover (5-HIAA/5-HT) could be valuable tools for prediction of suicidality and potential markers for evaluating major depressive disorder. NPY was perhaps a marker for first episode depression.

Topics: Adult; Aged; Depressive Disorder, Major; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Neuropeptide Y; Serotonin; Spinal Puncture

To investigate a possible link between some neuropeptides and depression, we analyzed their mRNA levels in brains of rats exposed to chronic mild stresses (CMS; a stress-induced anhedonia model), a commonly used model of depression. Rats exposed for 3 weeks to repeated, unpredictable, mild stressors exhibited an increased self-stimulation threshold, reflecting the development of an anhedonic state, which is regarded as an animal model of major depression. In situ hybridization was employed to monitor mRNA levels of neuropeptide Y (NPY), substance P and galanin in several brain regions. In the CMS rats, NPY mRNA expression levels were significantly decreased in the hippocampal dentate gyrus but increased in the arcuate nucleus. The substance P mRNA levels were increased in the anterodorsal part of the medial amygdaloid nucleus, in the ventromedial and dorsomedial hypothalamic nuclei and the lateral hypothalamic area, whereas galanin mRNA levels were decreased in the latter two regions. These findings suggest a possible involvement of these three peptides in mechanisms underlying depressive disorders and show that similar peptide changes previously demonstrated in genetic rat models also occur in the present stress-induced anhedonia model.

Topics: Amygdala; Animals; Arcuate Nucleus of Hypothalamus; Brain; Brain Mapping; Chronic Disease; Dentate Gyrus; Depressive Disorder, Major; Disease Models, Animal; Galanin; Gene Expression Regulation; Hypothalamus; Male; Neuropeptide Y; Neuropeptides; Rats; Rats, Wistar; RNA, Messenger; Self Stimulation; Stress, Psychological; Substance P

It has been hypothesized that the neuropeptide Y (NPY) system is involved in the pathogenesis of mood disorder. In this study, Y(1) and Y(2) receptor mRNA expression levels were analyzed in the dorsolateral prefrontal cortex of subjects affected with major depression, bipolar disorder, or schizophrenia and compared to normal controls. No significant alterations in Y(1) or Y(2) mRNA expression levels were observed between the groups. However, the Y(2) mRNA expression was elevated in layer IV in subjects with suicide as a cause of death. For the Y(1) mRNA expression, there was a negative correlation with increasing subject age in the prefrontal cortex. Analysis of covariance revealed a significant elevation of the Y(1) mRNA expression levels in individuals with a current history of marijuana use but no other drug. In summary, the current results suggest distinct alterations of the prefrontal Y(1) and Y(2) neuronal populations in aging and suicide.

Topics: Adult; Aged; Aging; Bipolar Disorder; Depressive Disorder, Major; Female; Gene Expression; Humans; Male; Middle Aged; Mood Disorders; Neurons; Neuropeptide Y; Prefrontal Cortex; Receptors, Neuropeptide Y; RNA, Messenger; Schizophrenia; Suicide