Pathogenesis Of Major Depression Research Articles

Life events and hippocampal volume in first-episode major depression

BackgroundThere are many studies on life events in depression and also several studies examining brain structural changes in the hippocampus of depressed patients. However, only few studies have focused on the association of life events and hippocampal volume in depression. The hypothesis of a significant negative association between life events and hippocampal volumes in first episode depression was examined. Methods28 in-patients with a first episode of major depression were examined with high-resolution magnetic resonance imaging measuring hippocampal volumes. The precourse of depression was assessed with the Interview for the Retrospective Assessment of the Onset and Course of Schizophrenia and Other Psychoses (IRAOS) and life events by using the Munich Interview for the Assessment of Life Events and Conditions (MEL). ResultsA significant negative correlation between major life events three month before the onset of depression and the left hippocampal volume was found for male patients. In female patients no significant association between major life events and hippocampal volumes could be found. ConclusionsThe results support the hypothesis that the hippocampus plays a crucial role in the pathogenesis of major depression in the early phase of the disorder particularly for male patients.

Reduced hippocampal volumes associated with the long variant of the tri‐ and diallelic serotonin transporter polymorphism in major depression

Substantial evidence supports a role for dysfunction of the serotonin transporter (5-HTT) in the pathogenesis of major depression. The polymorphism of the serotonin transporter gene (5-HTTLPR) was found to be associated with reduced hippocampal volume in major depression. However, the original diallelic polymorphism was criticized, because the L-allele can be subtyped into La and Lg alleles, the latter of which is thought to be similar to the S-allele. Therefore, the study aim was to examine the influences of the triallelic (La-Lg-S system) and diallelic 5-HTTLPR on hippocampal volumes in patients with major depression and healthy controls. Using high-resolution MRI hippocampal volumes and polymorphisms (5-HTTLPR) were measured in 60 in-patients with major depression and 60 healthy controls. Patients with the La/La genotype had significantly smaller hippocampal gray and white matter than La/La controls. No significant differences were found between patients and controls with La/(Lg + S) or (Lg + S)/(Lg + S) genotype. Moreover, within the patient group the La/La homozygous genotype had significantly smaller hippocampal white matter volumes than the La/(Lg + S) or (Lg + S)/(Lg + S) genotype. In conclusion, with the diallelic as well as the triallelic system the homozygosity for the long-allele is associated with decreased hippocampal volumes in patients with major depression, but not in healthy controls, suggesting that disease or stress specific processes linked to the serotonergic system may enhance the vulnerability to morphological alterations.

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

The HTR1A -1019C>G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A -1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD=4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression.

Glucocorticoid Receptor Gene Polymorphisms in Premenopausal Women with Major Depression

Glucocorticoid receptor gene polymorphisms are associated with glucocorticoid hypersensitivity and visceral obesity. Perturbations in HPA axis sensitivity to glucocorticoids implicated in the pathogenesis of major depression may result from functional alterations in the glucocorticoid receptor gene. We 1) examined the prevalence of genotype distribution of specific polymorphisms of the glucocorticoid receptor gene (Bcl1, N363S, rs33388, rs33389) in a subset of women from the P.O.W.E.R. Study (which enrolled 21- to 45-year-old premenopausal women with major depression and healthy controls) and 2) explored whether such polymorphisms were associated with visceral obesity and insulin resistance. Women with major depression had a higher body mass index, a higher waist:hip ratio, and more body fat than did controls. No differences were observed in plasma and urinary cortisol or in insulin sensitivity. The G/G genotype of the Bcl1 polymorphism was significantly more common (p<0.03) in women with major depression (n=52) than in controls (n=29). In addition, GG homozygotes (depressed n=10; controls n=2) had higher waist:hip ratios than did non-GG carriers (p<0.02). N363S, rs33388, and rs33389 polymorphisms were not different between groups. In conclusion, premenopausal women with both major depression and the GG genotype of the Bcl1 polymorphism had greater abdominal obesity compared with non-GG carriers.

The tryptophan hydroxylase (TPH) 2 gene unlike TPH-1 exhibits no association with stress-induced depression

BackgroundSerotonin (5-HT) has been implicated in the pathophysiology of several psychiatric disorders including major depression (MD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), and might be related to the pathogenesis of MD. Two isoforms are known, TPH-1 and TPH-2. Their association with MD is still debated. MethodsA case-control design was used for candidate gene-disease association in 194 patients with stress-induced MD, and 246 healthy controls, all North European Caucasians. Five TPH-2 polymorphisms were analyzed in terms of genotype, allele, and haplotype-based associations. ResultsNeither single marker nor haplotype-based analyses showed significant associations between TPH-2 and MD. LimitationsThe interpretations are limited by the restricted population size. ConclusionsThere was no association between TPH-2 gene variants and MD in the same population that had shown a strong association with TPH-1. Hence, the results suggest that in this particular group of stress-induced depression patients TPH-1 appears to be more relevant to MD pathogenesis than TPH-2.

The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-Americans

The hypothesis that brain-derived neurotrophic factor (BDNF) is involved in the pathogenesis of major depression is supported by several research findings; however, genetic studies assessing the relationship between BDNF and psychiatric disorders have produced conflicting results. We examined the effect of a BDNF polymorphism on depression susceptibility in Mexican-Americans. The single nucleotide polymorphism (Val66Met), which has been shown to have functional and behavioral effects, was genotyped in 284 depressed participants and 331 controls, showing association with depression (P=0.005). Individuals homozygous for the major allele (GG) had an increased chance of being depressed (OR=1.7 95% CI 1.17-2.47). Our findings support the association of BDNF single nucleotide polymorphism rs6265 and depression, suggesting that this polymorphism may increase susceptibility to major depression in Mexican-Americans.

Neurogenesis and major depression: implications from proteomic analyses of hippocampal proteins in a rat depression model

Major depression is one of the most disabling disorders. Yet, the pathogenesis of this mental disorder is poorly understood. Hippocampus is generally believed to be associated with pathogenesis of depression. In this study, we adopted a proteomic approach to examine possible alterations of protein expression in the hippocampus of a rat depression model. Our results suggest that neurogenesis in hippocampus may play an important role in the pathogenesis of major depression.

Cytokines and serotonin transporter in patients with major depression

Altered cytokine secretion as a mechanism in the etiology of depression is still obscure. The serotonin transporter (5-HTT) may play an important role in the termination of serotonergic neurotransmission by serotonin (5-HT) uptaking into presynaptic neurons and representing as an initial action site for selective 5-HTT reuptake inhibitors (SSRI). In our study, we evaluated whether cytokines and 5-HTT acted as biological markers for depression. Blood samples were collected from 42 participants. The differences in cytokine and 5-HTT mRNA expressions of leukocytes were assessed between the patients with major depression ( n = 20) and the healthy controls ( n = 22), along with the measurements prior and after treatment with a SSRI, fluoxetine, for 3 months in the follow-up patient group ( n = 8). The results revealed that the mRNA expressions of IL-1β, IL-6, IFNγ, TNFα, and 5-HTT were higher in the depressed patients than those of the healthy controls. The higher level of mRNA expressions of IFNγ and 5-HTT diminished after fluoxetine treatment. Furthermore, we found a positive correlation between 5-HTT and cytokines mRNA expressions in total participants, which suggested that pro-inflammatory cytokines and 5-HTT might play critical roles in the pathogenesis of major depression and that their levels were affected by chronic treatment with 5-HTT inhibitors.

Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters

Background Studies suggest that the dopaminergic system is involved in the pathogenesis of major depression, Axis II disorders, and suicidal behavior. Depressed suicide attempters constitute a heterogenous group and important differences may exist between depressed suicide attempters with or without Axis II disorders. Therefore, we compared demographic and clinical parameters, and cerebrospinal fluid (CSF) homovanillic acid (HVA) levels in depressed suicide attempters without comorbid Axis II disorders, depressed non-attempters without comorbid Axis II disorders, and normal controls. Methods Thirty-one depressed subjects with a history of a suicide attempt, 27 depressed subjects without a history of a suicide attempt, and 50 healthy controls were included in the study. Subjects with comorbid Axis II disorders were excluded. Demographic and clinical parameters, and CSF HVA levels were examined. Results The two depressed groups did not differ with regard to depression, aggression, hopelessness, and total hostility scale scores. Depressed suicide attempters had higher current suicidal ideation scores compared to depressed non-attempters. Depressed suicide attempters had lower CSF HVA levels compared to depressed non-attempters ( t = 4.4, df = 56, p < 0.0001) and to controls ( t = − 4.09, df = 79, p < 0.0001). There was no difference in CSF HVA levels between depressed non-attempters and controls ( t < 1, df = 75, NS). Conclusions Dopaminergic abnormalities are associated with suicidality but not with depression. The variability in the rates of comorbid Axis II disorders and in the prevalence of suicide attempters in different patient populations may affect both clinical and biological results of studies of mood disorders.

The possible role of tissue-type plasminogen activator and the plasminogen system in the pathogenesis of major depression

Major depressive disorder (MDD) is one of the most common psychiatric illnesses with an unknown etiology. Evidence from animal and human studies has suggested that brain-derived neurotrophic factor (BDNF) function may be implicated in the pathogenesis of MDD. Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that catalyses the generation of zymogen plasminogen from the proteinase plasmin. Recent studies have found that the proteolytic cleavage of proBDNF, a BDNF precursor, to BDNF by the plasmin represents a mechanism by which the direction of BDNF action is controlled. Furthermore, studies using mice deficient in tPA has demonstrated that tPA is important for the stress reaction, a common precipitating factor for MDD. A study of the serum levels of the plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of tPA, found that women with MDD had a higher PAI-1 concentration than normal controls. From these findings, it is proposed that the tPA/plasminogen system may play a role in the pathogenesis of MDD. Attempts to confirm the tPA/plasminogen hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention of this disorder.

Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder

Serotonin systems appear to play a key role in the pathogenesis of major depression and the therapeutic mechanisms of antidepressants. The firing rate of dorsal raphe serotonergic neurons is controlled by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors, and desensitization of these receptors is implicated in the antidepressant mechanism of selective serotonin reuptake inhibitors. We tested whether a functional polymorphism (C-1019G) in the promoter region of the HTR1A gene and serotonin-related genetic variants are related to fluoxetine antidepressant effect. We genotyped the HTR1A C-1019G polymorphism as well as polymorphisms in the serotonin transporter gene-linked polymorphic region (SERTPR), variable-number tandem-repeat polymorphisms in intron 2 (STin2) of the serotonin transporter gene, serotonin 2A receptor (T102C), tryptophan hydroxylase (A218C), and G-protein beta3 subunit (C825T) in 224 Chinese patients from southern Taiwan with major depression, who accepted 4-week fluoxetine treatment and therapeutic evaluation. Our results demonstrated that the HTR1A -1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response. The major limitation of this study is the lack of a placebo control. Future prospective study with placebo control may help to predict and individualize antidepressant treatment.

NBI 30775 (R121919), an orally active antagonist of the corticotropin‐releasing factor (CRF) type‐1 receptor for the treatment of anxiety and depression

AbstractSince the discovery of corticotropin‐releasing factor (CRF), extensive research has attempted to provide novel treatment strategies for diseases related to the malfunctions of the hypothalamic–pituitary–adrenocortical (HPA) system. In depression, cerebrospinal fluid levels of CRF are higher than that in normal individuals. Specifically, increased CRF signaling via the CRF1 receptor is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of compounds have been in various stages of development targeting the postulated overactivity of CRF/CRF1‐receptor signaling. NBI 30775, also known as R121919, is a potent, selective, and functional antagonist of the human CRF1 receptor that was being developed as a potentially novel treatment for anxiety and depression. In pharmacological assays in vitro, NBI 30775 was shown to be a potent functional antagonist at the CRF1 receptor, while having little affinity at the CRF2 receptor subtype. In animal studies, this translated into central CRF1 receptor inhibition determined by ex vivo binding studies. NBI 30775 was able to reduce stress‐induced elevations of plasma ACTH. It also exhibited behavioral effects in several animal models measuring both anxiety and depression, which included elevate plus maze, defense withdrawal, and tail suspension tests. Finally, in an open‐label dose‐escalation Phase 2a clinical study in patients with major depressive disorder, NBI 30775 was able to reduce the scores on self‐rated or physician‐administered depression scales in the patients. Although there were no untoward effects seen in the Phase 2a study, the clinical development of this compound was discontinued because of a reversible elevation of liver enzyme activity in two healthy volunteers in a parallel Phase I dose‐escalation study. This first clinical experience has certainly had a positive impact in the efforts to find a safe CRF1 receptor antagonist as a novel therapeutic for depression‐ and anxiety‐related disorders. Drug Dev. Res. 65:216–226, 2005. © 2005 Wiley‐Liss, Inc.

Protein kinase C substrate activators: potential as novel antidepressants

AbstractDepression and mood disorders are major public health concerns. Emerging evidence suggests that abnormal functions of protein kinase C (PKC) isozymes, ubiquitous in the central nervous system, may play a critical role in the pathogenesis of major depression and mood disorders. PKC activity and expression in the brain regions that are involved in mood regulation are reduced in suicide victims and are sensitive to stress‐related damage. PKC isozyme dysfunction may contribute to mood dysfunction, while PKC activators exhibit antidepressant pharmacology. Restoration of PKC activity thus represents an important therapeutic goal in antidepressant therapy. PKC substrate activators, therefore, may have important therapeutic value for the treatment of depression, especially when fine‐tuning of selective isoform activity can be effectively achieved pharmacologically. The success of antidepressant therapy with bryostatin‐1‐like agents that act on PKC signaling cascades depends on whether such agents at their effective doses would significantly disrupt or interfere with other vital functions that rely on a narrow range of PKC activities. Drug Dev. Res. 65:156–169, 2005. © 2005 Wiley‐Liss, Inc.

Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression.

In order to explore the MRI volume of the amygdala and hippocampus in patients with major depression, quantitative MRI of the amygdala and hippocampus were studied in 22 patients with major depression and compared with 13 age-matched controls. The results showed that both groups exhibited similar significant hippocampal asymmetry (left smaller than right). The volume of the bilateral hippocampus was significantly smaller in the major depression group than that in control group. The patients had significant asymmetry of the amygdalar volumes (right smaller than left). No correlation was found between hippocampal volume abnormalities and ill duration. It was concluded that the hippocampus and amygdala within limbic-cortical networks may play a crucial role in the pathogenesis of major depression.

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression

Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.

Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression.

Substantial evidence supports a role for dysfunction of the serotonin transporter in the pathogenesis of major depression. Several studies have found reciprocal interactions between the serotonergic system and both brain-derived neurotrophic factor and glutamate, which are known to modulate or affect hippocampal morphologic characteristics. To examine the influence of a polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene on hippocampal volumes in patients with major depression and healthy controls. Baseline investigation of a prospective magnetic resonance imaging study with a 4-year follow-up period. We examined 40 inpatients with major depression as well as 40 healthy controls matched for age, sex, and handedness. Subjects underwent high-resolution magnetic resonance imaging. Furthermore, genotyping for the 5-HTTLPR biallelic polymorphism was performed, which consists of a 44-base pair insertion (L allele) or deletion (S allele). Patients with the L/L homozygous genotype had significantly smaller hippocampal gray matter (left hemisphere: P=.003; right hemisphere: P=.01) and white matter volumes (left hemisphere: P=.001; right hemisphere: P=.002) than controls with this genotype. No significant differences were found between patients and controls with the L/S or S/S genotype. Moreover, patients with the L/L genotype had significantly smaller hippocampal white matter volumes than those with the L/S or S/S genotype (P=.03). These findings suggest that homozygosity for the L allele is associated with decreased hippocampal volumes in patients with major depression but not in healthy controls. A possible explanation is that the interaction between the serotonergic system and neurotrophic factors as well as excitatory amino acid neurotransmission may affect hippocampal morphologic characteristics.

Volumetric MRI analysis of the amygdala and the hippocampus in patients with major depression

In order to explore the MRI volume of the amygdala and hippocampus in patients with major depression, quantitative MRI of the amygdala and hippocampus were studied in 22 patients with major depression and compared with 13 age-matched controls. The results showed that both groups exhibited similar significant hippocampal asymmetry (left smaller than right). The volume of the bilateral hippocampus was significantly smaller in the major depression group than that in control group. The patients had significant asymmetry of the amygdalar volumes (right smaller than left). No correlation was found between hippocampal volume abnormalities and ill duration. It was concluded that the hippocampus and amygdala within limbic-cortical networks may play a crucial role in the pathogenesis of major depression.

Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression

Major depressive disorder (MDD) is a common mental disease with unknown etiology. Recent studies have suggested that decreased brain-derived neurotrophic factor (BDNF) may be implicated in the pathogenesis of MDD. Instead of a decrease in central BDNF, however, studies utilizing genetic depression animal models have found elevated levels of the factor. In the brain, BDNF exerts its influence chiefly by signaling through tyrosine receptor kinase B (Trk-B). In this report, it is suggested that Trk-B pathway down-regulation may be the major pathogenesis for MDD, while stress, which may reduce central BDNF, acts as a precipitation factor to further dampen central BDNF activity and contribute to the development of depression. Further, several possible mechanisms of Trk-B pathway down-regulation, and the implications for this down-regulation in MDD are discussed.

Is mania caused by overactivity of central brain-derived neurotrophic factor?

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems, as well as the intracellular signal-transduction pathway. Recent studies had demonstrated that BDNF may play a role in the antidepressant mechanism and the pathogenesis of major depression. These findings implicated that BDNF may involve in mood regulation. In addition, (1) studies found positive association between BDNF genetic polymorphism and bipolar affective disorders; (2) agents which potentially induce manic states also increase BDNF, and (3) increase in mossy fibers were noted for bipolar affective disorder brain and BDNF is related to the induction of aberrant mossy fiber sprouting. From these finding, it is proposed that BDNF overactivity may be implicated in the manic state. The notion of BDNF overactivity in mania suggests that factors associated with increased BDNF activity may proffer the etiological fundamentals for bipolar affective disorder. Further, exploration of this hypothesis can provide a new direction in the treatment of the bipolar affective disorder.

Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects

A dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) system has been hypothesized to account for a myriad of cardinal symptoms of affective disorders. Specifically, increased CRH signalling via CRH type 1 receptors is thought to be an important factor in the pathogenesis of major depression and anxiety disorders. Consequently, a number of drugs have been developed in order to target the postulated increase in CRH/CRH 1 receptor signalling. One of these compounds, R121919, binds with high affinity to CRH1 receptors antagonising the action of CRH. R121919 was recently tested in an open-label study conceptualized as a safety and tolerability study. As part of this study, a thorough endocrine evaluation and detailed clinical laboratory analysis were assessed several times during 30 days of treatment with two different dose regimens of R121919 (5–40 mg vs. 40–80 mg) in 24 patients with a major depressive episode. During treatment with the experimental drug no serious side effects were noted. In particular, there were no adverse effects or impairment of the hypothalamic–pituitary–gonadal system, the hypothalamic–pituitary–thyroid axis, the renin–angiotensin system, prolactin or vasopressin secretion. Furthermore, no changes in the serum corticotropin and cortisol concentrations and in the responsivity of corticotropin and cortisol following a CRH stimulation test were noted. No effects of R121919 on clinical laboratory parameters including liver enzymes, EEG and ECG were observed. These results encourage the development of other CRH-1-R antagonists as a novel class of antidepressive drugs.