Pathogenesis Of Major Depression Research Articles

Genetics of Serotonin Receptors and Depression: State of the Art

Major depression (MD) is a major health problem, partly due to the incomplete understanding of the pathogenic mechanisms of the disease. Research efforts have mainly focused on alterations in monoaminergic neurotransmission, especially in relation to the serotonergic system, due to its key role in the regulation of mood and related biological functions. Given the high heritability of MD (estimated between 31% and 42% for unipolar depression), genes coding for key regulators of the serotonergic neurotransmission have been considered as optimal candidates. The present review is focused on the role of genes coding for serotonin receptors in MD pathogenesis, since the serotonin transporter and enzymes involved in serotonin metabolism have been reviewed elsewhere. Despite the large number of candidate gene studies focusing on genes coding for serotonin receptors, results have been inconsistent. The most replicated findings are the associations between rs6295 (HTR1A gene) G allele or G/G genotype and rs6311 (HTR2A gene) A allele or A/A genotype and MD or depressive symptoms. Preclinical and imaging/post-mortem studies in humans provide strong support for the involvement of HTR1A and HTR2A genes in MD. Nevertheless, the inconsistency across previous studies clearly suggests that innovative approaches should be designed in order to overcome the limitations of candidate gene studies. To date, the most appealing methodologies seem to be full exome or genome sequencing, genome-wide pathway analyses, endophenotypes, and epigenetic biomarkers. The reported tools may assist in the detection of multiple-loci models, which could potentially explain the high percentage of MD susceptibility ascribed to genetic factors.

Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment

The endocannabinoid system has been implicated in the pathogenesis of major depression (MD) as well as in the mediation of antidepressant drug effects. To analyze CNR1 gene variants in MD and clinical response to citalopram (selective serotonin re-uptake inhibitors [SSRI]). The role of CNR1 gene (rs806368, rs1049353, rs806371, rs806377 and rs1535255) was investigated in 319 outpatients with MD and 150 healthy individuals. A subsample of 155 depressive patients were treated with citalopram and evaluated for response (fourth week) and remission (12th week) by the 21-item Hamilton Depression Rating Scale (HDRS). We observed a higher frequency of rs806371 G carriers in MD patients with both presence of melancholia (p = 0.018) and psychotic symptoms (p = 0.007) than in controls. Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368-rs1049353-rs806371) (p = 0.008). This haplotype finding was consistent when we compared controls with MD subsample stratified by melancholia (p = 0.0009) and psychotic symptoms (p = 0.014). The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers (p = 0.008 and 0.012, respectively). Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 (p = 0.032). Also, we observed significant effect of time-sex-genotype interaction for the rs806368, showing that the C carrier men presented a better response to antidepressant treatment throughout the follow-up than TT homozygous men and women group (p = 0.026). These results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram.

Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice

Estradiol decline has been associated with depressive-like behavior in female mice and NO has been suggested to play a major role in the pathogenesis of major depression. This study was conducted to investigate the antidepressant-like effects of acute estradiol administration in female ovariectomized (OVX) mice and the possible role of nitric oxide (NO)/cyclic GMP (cGMP) pathway. To this end, bilateral ovariectomy was performed in female mice and different doses of estradiol were injected alone or in combination with non-specific NO synthase (NOS) inhibitor (l-NAME), selective neural NOS (nNOS) inhibitor (7-NI), an NO precursor (l-arginine) or selective phosphodiesterase type 5 inhibitor (sildenafil). The duration of immobility was recorded in the forced swimming test (FST) to assess the depressive behavior. Moreover, hippocampal levels of NO were determined in select groups. 10days following the procedure, OVX mice showed significantly prolonged immobility time in comparison with the sham group. Estradiol (3, 10, and 30μg/kg, s.c.), when injected 1h prior to FST, exerted antidepressant-like effects in OVX mice. Both l-NAME (30mg/kg, i.p.), and 7-NI (50mg/kg, i.p.) significantly reduced the immobility times of OVX mice. Administration of a sub-effective dose of l-NAME (10mg/kg), 15min after a sub-effective dose of estradiol (1μg/kg, s.c.) had a robust antidepressant-like effect in OVX mice. Also a sub-effective dose of 7-NI (25mg/kg), 30min after a sub-effective dose of estradiol (1μg/kg, s.c.) showed antidepressant-like effect in OVX mice. Both the NO precursor l-arginine (750mg/kg, i.p.) and the cGMP-specific phosphodiesterase type 5 inhibitor sildenafil (5mg/kg, i.p.), 30min before estradiol treatment, prevented the antidepressant-like effect of a potent dose of estradiol (10μg/kg, s.c.) in OVX mice. The present findings suggest that suppression of the NO synthase/NO/cGMP pathway may be involved in the antidepressant-like effects of estradiol in OVX mice.

Effects of apolipoprotein E genetic polymorphism on susceptibility of depression and efficacy of antidepressants

To assess the effects of apolipoprotein E (APOE) polymorphism on the susceptibility of depression and the efficacy of antidepressants. A total of 275 patients with depression, who met the diagnostic criteria of both CCMD-3 and DSM-4, were randomly assigned into venlafaxine group (n=136)and paroxetine group(n=139). Another 202 healthy subjects were enrolled as the control group. Hamilton Rating Scale for Depression (HAMD)-17 was adopted as the primary rating instrument to evaluate the severity of depression on the baseline and the end of the 1st, 2nd, 4th, 6th week after treatment, respectively. HAMD scores ≤7 was defined as remission, and the reduction of HAMD scores ≥50% was defined as response while <50% was defined as invalid. PCR-restriction fragment length polymorphisms (PCR-RFLP) was applied to detect the genetic polymorphism of the APOE in the case groups and control group. In the venlafaxine group, the remission rate was 52.9%(n=72), the response rate was 26.5%(n=36), and the invalid rate was 20.6%(n=28), whereas the corresponding data in the paroxetine group wee 42.4%(n=59), 31.7%(n=44), and 25.9% (n=36), respectively. There were no significant differences in the efficacy between the two groups(p>0.05). In the venlafaxine group, there were no significant differences in the genotypes and the allele distribution frequency of APOEΕ2/Ε3/Ε4 between the remitters, nonremitters, and healthy controls at the end of the 6th week(p>0.05), but there was significant differences in the allele distribution frequency between the nonremitters and healthy controls(p=0.02). In paroxetine group, there were no significant differences in the genotypes and the allele distribution frequency of APOEΕ2/Ε3/Ε4 among the remitters, nonremitters and healthy controls at the end of the 6th week(p>0.05), but there were significant differences in the allele distribution frequency between the nonremitters and healthy controls (p=0.04); in addition, there were also significant differences in Ε2/Ε3 and Ε4 allele between the two groups (p=0.014). The APOE gene may not play a major role in the pathogenesis of major depression. The efficacy of venlafaxine is same as paroxetine after treatment for six weeks. The APOE (Ε2+Ε3) allele may be an indicator of the bad efficacy of paroxetine treatment.

Acute administration of Zn, Mg, and thiamine improves postpartum depression conditions in mice.

Postpartum depression (PPD) affects approximately half of new mothers. Chronic exposure to progesterone during pregnancy and its withdrawal following delivery increases depression and anxiety. In addition, there are complex interactions between hormones, neurotransmitters, and trace elements. Zinc (Zn) and magnesium (Mg) influence the nervous system by impacting synaptic neurotransmission in the brain. Thiamine (Vit B1) deficiency results in a high percentage of depressive behaviors. Elevated levels of reactive oxygen species in pregnancy are implicated in the pathogenesis of major depression. We examined the effects of different combinations of Zn, Mg, and Vit B1 in an animal model of PPD. ZnCl, MgCl, and thiamine-HCl were administered to PPD-induced mice. Depression, anxiety-related behavior, and total antioxidant capacity (TAC) were assessed. Depression and anxiety-like behavior were evaluated by the forced swimming test (FST) and elevated plus-maze, respectively. The acute combined administration of Zn, Mg, and Vit B1 significantly decreased immobility time in FST, increased the percentage of both time spent in- and entries to open arms in the elevated plus-maze, and augmented TAC. Our data suggest that acute administration of combined treatment with Zn, Mg, and Vit B1 on postpartum day 3 improves depressive symptoms and anxiety-like behaviors. Our evaluation of TAC is in accordance with behavioral results.

MicroRNA Expression Is Down-Regulated and Reorganized in Prefrontal Cortex of Depressed Suicide Subjects

BackgroundRecent studies suggest that alterations in expression of genes, including those which regulate neural and structural plasticity, may be crucial in the pathogenesis of depression. MicroRNAs (miRNAs) are newly discovered regulators of gene expression that have recently been implicated in a variety of human diseases, including neuropsychiatric diseases.Methodology/Principal FindingsThe present study was undertaken to examine whether the miRNA network is altered in the brain of depressed suicide subjects. Expression of miRNAs was measured in prefrontal cortex (Brodmann Area 9) of antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) using multiplex RT-PCR plates. We found that overall miRNA expression was significantly and globally down-regulated in prefrontal cortex of depressed suicide subjects. Using individual tests of statistical significance, 21 miRNAs were significantly decreased at p = 0.05 or better. Many of the down-regulated miRNAs were encoded at nearby chromosomal loci, shared motifs within the 5′-seeds, and shared putative mRNA targets, several of which have been implicated in depression. In addition, a set of 29 miRNAs, whose expression was not pairwise correlated in the normal controls, showed a high degree of co-regulation across individuals in the depressed suicide group.Conclusions/SignificanceThe findings show widespread changes in miRNA expression that are likely to participate in pathogenesis of major depression and/or suicide. Further studies are needed to identify whether the miRNA changes lead to altered expression of prefrontal cortex mRNAs, either directly (by acting as miRNA targets) or indirectly (e.g., by affecting transcription factors).

Young Women With Major Depression Live on Higher Homeostatic Sleep Pressure Than Healthy Controls

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75–25 Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement. (Author correspondence: Christian.cajochen@upkbs.ch)

Characterization of serotonin neurotransmission in knockout mice: implications for major depression

The interaction between genes and environment plays a significant role in the pathogenesis of major depression and mood disorders. Preclinical and clinical studies have established that a dysfunction of serotonin (5-HT) neurotransmission is a common hallmark in major depression and drugs acting on the 5-HT system have antidepressant properties. In the past 15 years, the development of knockout mice showing a depressive-like or resilience-like phenotype have allowed us to better understand the complex relationship between genes, behaviour and the 5-HT system in mood disorders. The present review revises several knockout mice genotypes with 'mood' alteration and analyses how 5-HT firing activity, measured with electrophysiological techniques, is impaired after a gene manipulation. The behavior and electrophysiology data from 5-HT transporter (5HTT), 5-HT₁(A), 5-HT₄, the neurokinin 1 (NK₁) receptor, fatty acid amide hydrolase (FAAH) and the TWIK-1 related K+ (TREK-1) channel knockout mice are here analysed. Interestingly, a correlation between 5-HT firing rate and depressive/resilience phenotypes can be established in these different knockouts. Furthermore, findings in knockout mice have been successfully translated to humans, and findings from human studies have helped to design and generate knockout mice to explore new hypotheses of the etiology of human depression. The correlation of 5-HT activity and behavior could be a predictor factor for understanding the role of receptors, channels and enzymes in depression, and could be used also to assess the potential antidepressive effects of novel drugs.

P-492 - Analysis of association serotonin transporter gene and antidepressant response to citalopram in iranian major depressive population

Introduction Serotonin systems play a key role in the pathogenesis of major depression, SSRIs drugs are the first step in its treatment. Serotonin transporter (5HTT) gene is known as the responsible gene for Major Depression Disorder. Deletion or insertion in the 5-HTTLPR creates short and long alleles. Detecting the genotype regulatory region in (5HTT) can be useful and individual for everybody antidepressant treatment. Objectives Western reports have demonstrated that l allele is associated with better SSRIs anti depressive effects than the s allele. Study of a Korea had contrasting finding. Aims There is association between treatment outcome phenotypes and HTTLPR in Iranian Major Depressive Population. Method In this study, 105 patients with MDD (according by DSM-IV-TR) treated by Citalopram. On the other hand genotyping for alles of 5HTT and level of drug serum was obtained. Beck depression test was done in the first, 4th and 8th week. Dose Citalopram was 20–60 mg/D. Lack of clinical response was studied with mental state and Beck Depression test, then if there was no response the drug changed.(after 4 weeks). Results In Iranian patients frequency of each allele base on the population study is near to 0.5 (L: 0.48 and S: 0.52). 69% of the patients with allele L (L/L or L/S) respond to Citalopram, while just 44% of the S/S patients did not need to change the drug. Conclusion our study confirms the hypothesis that the L allele is associated with better response to antidepressant drug (P value=0.033. CI: 95%).

Individual Stress Vulnerability Is Predicted by Short-Term Memory and AMPA Receptor Subunit Ratio in the Hippocampus

Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function.

Thyroid autoimmunity and treatment response to escitalopram in major depression

Background: There is evidence that immune alterations play an important part in the pathogenesis of major depression. Thyroid autoimmunity has been found in association with major depression in several studies. Aim: 1) to examine whether the prevalence of anti-thyroid peroxidase autoantibodies (anti-TPO) in depressive patients differs from that in healthy controls; 2) to investigate the possible relationship between thyroid autoimmunity, total T3, free T3, free T4, thyroid-stimulating hormone (TSH), clinical status and treatment outcome in depression. Method: The study group consisted of 129 outpatients (69.8% female; mean age 31.7±12.0 years) with major depressive disorder with a Montgomery–Åzsberg Depression Rating Scale total score of 22 or higher and 72 healthy controls (62.5% female; mean age 31.7±13.1 years). The patients were treated with escitalopram 10–20 mg/day for 12 weeks using open-label placebo non-controlled design. Anti-TPO, total T3, free T3, free T4 and TSH were measured before the treatment. Results: The anti-TPO was found in eight (8.9%) depressive and two (4.8%) healthy females without statistical difference between these groups. Since anti-TPO was not seen in males, all further statistical analyses were carried out in females. At the end of week 12 of the treatment, 60 female patients (66.7%) were defined as responders and 30 depressive females (33.3%) showed insufficient response to treatment. Although there were no significant differences in the measurements between responders and non-responders, the last group showed a trend for a higher prevalence of anti-TPO compared with responders. Conclusion: Thyroid autoimmunity might be a factor predicting treatment response to antidepressants in depressive patients.

Effects ofBDNFPolymorphisms on Antidepressant Action

Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidepressant treatment and since genetic factors may contribute to this inter-individual variability in antidepressant response, pharmacogenetic studies have tested the associations between genetic polymorphisms in candidate genes related to antidepressant therapeutic action. In human BDNF gene, there is a common functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF. Because of the potentially important role of BDNF in the antidepressant mechanism, many pharmacogenetic studies have tested the association between this polymorphism and the antidepressant therapeutic response, but they have produced inconsistent results. A recent meta-analysis of eight studies, which included data from 1,115 subjects, suggested that the Val/Met carriers have increased antidepressant response in comparison to Val/Val homozygotes, particularly in the Asian population. The positive molecular heterosis effect (subjects heterozygous for a specific genetic polymorphism show a significantly greater effect) is compatible with animal studies showing that, although BDNF exerts an antidepressant effect, too much BDNF may have a detrimental effect on mood. Several recommendations are proposed for future antidepressant pharmacogenetic studies of BDNF, including the consideration of multiple polymorphisms and a haplotype approach, gene-gene interaction, a single antidepressant regimen, controlling for age and gender interactions, and pharmacogenetic effects on specific depressive symptom-clusters.

Molecular pathogenesis of major depression: The relationship between oligodendrocyte dysfunctions and chronic stress exposure

Molecular pathogenesis of major depression: The relationship between oligodendrocyte dysfunctions and chronic stress exposure

Opposite effects of milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of nitric oxide and brain-derived neurotrophic factor in mouse brain cortex

There is a growing body of evidence demonstrating that changes in the brain levels of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) are implicated in the pathogenesis of major depression. We report here the effects of subchronic treatment of mice with milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of NO and BDNF in mice. In vivo administration of milnacipran (10 mg/kg) for 14 days caused a significant decrease in nitrate and nitrite concentrations in the cerebral cortex and hippocampus, but not in the midbrain. Milnacipran (10 mg/kg, 14 days) also decreased the activity of NO synthase in the cerebral cortex. On the other hand, milnacipran (10 mg/kg, 14 days) increased the levels of BDNF protein and mRNA in the cerebral cortex. These findings suggest that milnacipran has opposite effects on the levels of NO and BDNF in the brain cortex, namely, downregulation of NO and upregulation of BDNF.

Negative emotionality: monoamine oxidase B gene variants modulate personality traits in healthy humans.

Monoamine oxidase A and B (MAOA and MAOB) appear to be involved in the pathogenesis of Major Depression, and vulnerability of Major Depression is associated with personality traits relating to positive and negative affect. This study aimed to investigate associations between MAOA and MAOB polymorphisms and personality traits of positive and negative emotionality in healthy volunteers, to elucidate mechanisms underlying personality and the risk for depression. Healthy Caucasian volunteers (N = 150) completed the Multiphasic Personality Questionnaire (MPQ), which includes independent superfactors of Positive Emotionality and Negative Emotionality. Participants were genotyped for 8 MAOA and 12 MAOB single nucleotide polymorphisms (SNPs). Association analyses for both SNPs and haplotypes were performed using the permutation approach implemented in PLINK. Negative Emotionality was significantly associated with the two highly linked MAOB polymorphisms rs10521432 and rs6651806 (p < 0.002). Findings were extended in haplotype analyses. For MAOB the 4-SNP haplotype GACG formed from rs1799836, rs10521432, rs6651806 and rs590551 was significantly related to lower Negative Emotionality scores (p < 0.002). MAOA was not related to personality in this study. Our finding provides the first evidence that MAOB polymorphisms influence levels of negative emotionality in healthy human volunteers. If confirmed, these results could lead to a better understanding of personality traits and inter-individual susceptibility developing psychiatric disorders such as major depression.

The Role of Serotonin in the Pathophysiology of Depression: As Important As Ever

Featured Article: Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994;40: 288–95.1 Fifteen years have elapsed since we published this article focusing on the serotonin transporter (SERT)2 . Although developed as a review, this report ultimately included original data from a large study of drug-free depressed patients and controls showing that platelet [3H]imipramine binding, the ligand of choice for labeling serotonin transporters, was significantly decreased in depression. We also showed data indicating that the decreased platelet [3H]imipramine binding was specific for major depression. The high number of citations, including numerous citations even in 2009, reflects the ongoing importance of serotonin in depression. Since this report was published, remarkable advances have occurred in our understanding of the molecular neurobiology of serotonergic neurons, and in functional brain imaging studies, which have provided further evidence for a preeminent role for serotonergic circuits in the pathogenesis of major depression and suicide (1). These advances include (a) the development of specific positron-emission tomography ligands for the SERT and their use in detecting alterations in serotonergic circuits in patients with major depression and suicidality, as well as quantifying the magnitude of SERT occupancy associated with antidepressant treatment; (b) functional polymorphism in the promoter region of …

Alpha-Synuclein mRNA Levels Correspond to Beck Depression Inventory Scores in Females with Eating Disorders

α-Synuclein (α-Syn) is a neuronal protein involved in the regulation of brain serotonin and dopamine levels. We analyzed the peripheral expression of α-Syn mRNA and Beck Depression Inventory scores in female patients suffering from anorexia nervosa (n = 18) or bulimia nervosa (n = 24). We found a significant positive association between α-Syn mRNA expression and the total scores of the Beck Depression Inventory (linear regression; R² = 0.20; p = 0.003). α-Syn may play a pathophysiological role in depressive symptoms associated with eating disorders. Further investigations in patients with depression as a sole diagnosis are needed to support its role in the pathogenesis of major depression.

Brain-Derived Neurotrophic Factor and Antidepressant Action: Another Piece of Evidence from Pharmacogenetics

EVALUATION OF: Gratacòs M, Soria V, Urretavizcaya M et al.: A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders. Pharmacogenomics J. 8, 101-112 (2008). The neurotrophin hypothesis of depression and antidepressant drug action postulates that reduced activity of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), plays an important role in the pathogenesis of major depression, and that its restoration may represent a critical mechanism underlying antidepressant therapeutic effect. This hypothesis is supported by numerous animal studies; however, evidence from clinical studies is lacking. This study is the first to use both single-marker as well as haplotype analysis to test the effect of genetic variants of BDNF on the therapeutic effects of antidepressant treatment in mood disorder. Among eight BDNF TagSNPs tested, one allele (rs908867) is associated with antidepressant response, with heterozygote carriers showing a better response than homozygous analog. The authors also identified a haplotype associated with the therapeutic response. This study provides clinical evidence to support the role of BDNF in antidepressant therapeutic mechanisms. However, further work is needed to confirm the findings, for several reasons. First, the study included not only major depression but also bipolar disorder patients; second, various antidepressants were used in this study, which could affect patients' responses; third, the frequency of the haplotype associated with treatment response is rare; and fourth, previous studies of the effects of single BDNF polymorphisms on antidepressant action have reported conflicting findings. Several suggestions for further work are discussed below.

Proteomic analysis of a rat model of depression

Major depression is one of the most disabling disorders, yet the pathogenesis of this mental disorder is poorly understood. The techniques of proteomics provide us with powerful tools, while the animal models of depression enable research that cannot be performed on humans due to practical difficulties or ethical reasons. In this review, we summarize the characteristics of some most commonly applied rat models of depression, and explore what could be done with novel proteomic approaches to offer an insight to the pathogenesis of major depression, biomarker establishment and drug development.

Association of MAO-A Variant with Complicated Grief in Major Depression

Background/Aims: It has been suggested that monoamine oxidase A (MAO-A) activity is involved in the pathogenesis of major depression. Bereavement-related complicated grief significantly increases the risk of major depression and has been shown to be influenced by serotonergic tonus, possibly conferred by MAO-A activity. Complicated grief – whose inclusion in DSM-V as a separate mental disorder is under discussion – has been shown to be a distinct syndrome with symptoms not seen in depression. Therefore, in the present study, genetic variation in the MAO-A gene was investigated for its influence on complicated grief in major depression. Methods: Sixty-six unrelated Caucasian patients (41 female, 25 male) with major depression and a history of bereavement were evaluated for complicated grief using the Inventory of Complicated Grief (ICG), the posttraumatic stress reaction after the loss by means of the Impact of Event Scale (IES-R) and further psychopathological measures. Patients were additionally genotyped for the functional variable number tandem repeat (VNTR) in the promoter region of the MAO-A gene. Results: The more active longer allele of the MAO-A VNTR was significantly associated with complicated grief in the female subgroup of patients (χ² = 9.471, p = 0.002, OR = 9.208, 95% CI 2.129–38.899, Bonferroni-corrected p = 0.012), whereas there was no such effect in male patients. Higher posttraumatic stress reaction was only nominally associated with the more active longer allele of the MAO-A VNTR in the female subgroup of patients (genotypes: χ² = 5.939, p = 0.015, OR = 5.333, 95% CI 1.366–20.557, Bonferroni-corrected p = 0.087). No significant associations of MAO-A VNTR with the severity of depressive symptoms (Beck Depression Inventory), anxiety symptoms (Spielberger State-Trait Anxiety Inventory), general mental health (Brief Symptom Inventory), or perceived social support (F-SozU) were found (all p > 0.10). Conclusion: The present pilot study for the first time suggests a gender-specific contribution of the more active MAO-A VNTR variant to an increased vulnerability for complicated grief as a potential intermediate phenotype of major depression.