Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and has been implicated in the pathogenesis of major depressive disorder (MDD) and in the mechanism of antidepressant action. This study aimed to investigate whether common genetic variation in the TPH2 gene is associated with MDD and therapeutic response to antidepressants in a Chinese population. A total of 508 MDD patients and 463 unrelated controls were recruited. Among the MDD patients, 187 accepted selective serotonin reuptake inhibitor (fluoxetine or citalopram) antidepressant treatment for 8 weeks with therapeutic evaluation before and after treatment. Five TPH2 polymorphisms were genotyped and their association with MDD or treatment response was assessed by haplotype and single-marker analysis. In single-marker-based analysis, the rs17110747-G homozygote polymorphism was found to be more frequent in the MDD patients than in the controls (P = 0.002). Genotype analysis in responders (defined as those with a 50% reduction in baseline Hamilton score) and non-responders after 8 weeks of antidepressant treatment showed that the proportion of rs2171363 heterozygote carriers was higher in the responders than the non-responders (P = 0.009). No significant association with MDD or antidepressant therapeutic response was discovered in haplotype analyses. Our findings show that TPH2 genetic variants may play a role in MDD susceptibility and in acute therapeutic response to selective serotonin reuptake inhibitors.     

Cyclic-AMP response element binding protein (CREB) in the neutrophils of depressed patients

Cyclic-AMP response element binding (CREB) protein regulates the expression of many genes involved in the pathophysiology of depression. Increased CREB levels were found in the brain of antidepressant-treated rats and decreased protein and mRNA expression of CREB was reported in the postmortem brain of depressed suicide victims. We determined CREB protein expression, using Western blot technique, and CRE-DNA binding, using gel shift assay, in neutrophils obtained from 22 drug-free patients with major depressive disorder (MDD) and 23 normal control subjects. Diagnosis of patients was based on Diagnostic and Statistical Manual of Mental Disorders DSM-IV criteria; severity of illness was rated by Hamilton Depression Rating Scale (HDRS). We found that the CRE-DNA binding activity and CREB protein expression were significantly decreased in the neutrophils of drug-free MDD patients compared with normal control subjects. Our findings suggest that CREB may play an important role in the pathophysiology of depression and that it may be an important target for the therapeutic action of antidepressant drugs. Neutrophil CREB levels may also serve as a useful biomarker for patients with MDD.     

Association study of serotonin 1B receptor (A-161T) genetic polymorphism and suicidal behaviors and response to fluoxetine in major depressive disorder

Serotonin 1B receptors (5-HT1B) are autoreceptors involved in the local inhibitory control of serotonin release, and have been suggested to play a role in the pathogenesis of major depressive disorder (MDD) and the antidepressant effects of the selective serotonin reuptake inhibitors in patients. We genotyped the 5-HT1B A-161T polymorphism in 160 patients with MDD and 160 normal controls. We then tested the hypothesis that the allelic variant, A-161T, of the 5-HT1B gene confers susceptibility to MDD or is associated with suicide attempt. We also examined the association of this polymorphism with therapeutic response in 116 of the MDD patients who received fluoxetine treatment for 4 weeks. No significant difference was found in the A-161T genetic polymorphism between MDD patients and controls. The genotype distribution between patients with and without suicide attempt, or between fluoxetine treatment responders and nonresponders were also similar. Our findings suggest that 5-HT1B A-161T genetic polymorphism does not play a major role in the susceptibility to MDD, nor is it related to suicidal attempt or the therapeutic response to fluoxetine in MDD.     

Decreased Total Antioxidant Activity in Major Depressive Disorder Patients Non-Responsive to Antidepressant Treatment

Objective

This study aimed to evaluate the total antioxidant activity (TAA) in patients with major depressive disorder (MDD) and the effect of antidepressants on TAA using a novel potentiometric method.

Methods

Twenty-eight patients with MDD and thirty-one healthy controls were enrolled in this study. The control group comprised 31 healthy individuals matched for gender, drinking and smoking status. We assessed symptoms of depression using the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI). We measured TAA using potentiometry. All measurements were made at baseline and four and eight weeks later.

Results

There was a significant negative correlation between BDI scores and TAA. TAA was significantly lower in the MDD group than in controls. When the MDD group was subdivided into those who showed clinical response to antidepressant therapy (response group) and those who did not (non-response group), only the non-response group showed lower TAA, while the response group showed no significant difference to controls at baseline. After eight weeks of antidepressant treatment, TAA in both the response and non-response groups was similar, and there was no significant difference among the three groups.

Conclusion

These results suggest that the response to antidepressant treatment in MDD patients might be predicted by measuring TAA.     

Alterations of microRNA-124 expression in peripheral blood mononuclear cells in pre- and post-treatment patients with major depressive disorder

Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p < 0.001), and that the area under the curve of miR-124 from ROC analysis was 0.762 with a sensitivity of 83.33% and specificity of 66.67% in distinguishing MDD patients from healthy controls. In addition, the expression levels of miR-124 were significantly down-regulated after eight weeks of treatment (p < 0.001). MiRNA target gene prediction and functional annotation analysis indicated that altered miR-124 was involved in affecting some important biological processes and pathways related to MDD. These results provide new information on miR-124 involvement in the biological alterations of MDD and in antidepressant effects.     

Case-control association study of 14 variants of CREB1, CREBBP and CREM on diagnosis and treatment outcome in major depressive disorder and bipolar disorder

Some evidence suggests an association between genetic variants within the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), CREB binding protein (CREBBP) and cAMP response element-modulator (CREM) and several psychiatric disorders. The present study investigated whether some single nucleotide polymorphisms (SNPs) within these genes could be associated with major depressive disorder (MDD) and bipolar disorder (BD) and whether they could predict clinical outcomes in Korean in-patients treated with antidepressants and mood stabilizers, respectively. The sample comprised 145 patients with MDD, 132 patients with BD and 170 psychiatrically healthy controls. Participants were genotyped for 14 SNPs within CREB1, CREBBP and CREM. Baseline and final clinical measures, including the Montgomery-?sberg Depression Rating Scale and Young Mania Rating Scale for patients with MDD and BD, respectively, were recorded. All p-values were 2-tailed, and statistical significance was conservatively set at the 0.006 level in order to reduce the likelihood of false positive results. We failed to observe any association of the 14 SNPs genotypes or alleles with clinical improvement, response and remission rates as well as final outcomes in any of such disorders. Our findings suggest that the 14 SNP under investigation in our study do not influence diagnosis and treatment response in patients with MDD and BD. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.     

Early improvement as a resilience signal predicting later remission to antidepressant treatment in patients with Major Depressive Disorder: Systematic review and meta-analysis

Early improvement of depressive symptoms during the first two weeks of antidepressant treatment has been discussed to be a resilience signal predicting a later positive treatment outcome in patients with Major Depressive Disorder (MDD). However, the predictive value of early improvement varies between studies, and the use of different antidepressants may explain heterogeneous results. The objective of this review was to assess the predictive value of early improvement on later response and remission and to identify antidepressants with the highest chance of early improvement. We included 17 randomized controlled trials investigating early improvement in 14,779 adult patients with MDD comparing monotherapy with an antidepressant against placebo or another antidepressant drug. 62% (range: 35–85%) of patients treated with an antidepressant and 47% (range: 21–69%) with placebo were early improver, defined as a >20%/25% symptom reduction after two weeks of treatment. Early improvement predicted response and remission after 5–12 weeks of treatment with high sensitivity (85%; 95%-CI: 84.3 to 85.7) and low to moderate specificity (54%; 95%-CI: 53.1 to 54.9). Early improver had a 8.37 fold (6.97–10.05) higher likelihood to become responder and a 6.38 fold (5.07–8.02) higher likelihood to be remitter at endpoint than non-improver. The highest early improver rates were achieved in patients treated with mirtazapine or a tricyclic antidepressant. This finding of a high predictive value of early improvement on treatment outcome may be important for treatment decisions in the early course of antidepressant treatment. Further studies should test the efficacy of such early treatment decisions.     

Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect.

BACKGROUND: Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect. METHODS: We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs. RESULTS: In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ. CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents.     

Effect of treatment on serum glial cell line-derived neurotrophic factor in depressed patients

Post-mortem studies have demonstrated a decreased number of glia, reduced glial density, and a decreased glia/neuron ratio in different brain areas of patients diagnosed with a major depressive disorder (MDD). Researchers have therefore suggested that neurotrophic growth factor systems might be involved in the aetiology of MDD. This study aimed to test whether glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor beta family, in serum was associated with MDD. Serum concentrations were measured in MDD patients before treatment (n=76), after 8 weeks of antidepressant treatment (n=39), and in control subjects (n=50) using a sandwich ELISA method. Serum GDNF was significantly lower in MDD patients before treatment than in control subjects (P<0.001). From baseline to remission after 8 weeks of treatment, the increase in serum GDNF was statistically significant (P<0.001). The present study suggests that lower serum GDNF might be involved in the pathophysiology of MDD and antidepressant treatment increases the GDNF in MDD.     

Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study

OBJECTIVE: Pilot study examining the effects of estrogen therapy (ET) on antidepressant response in postmenopausal women with major depressive disorder (MDD). METHODS: Twenty-two subjects received sertraline at 50mg/day for one week, with an increase to 100mg/day at week 2 for a 10-week trial. Transdermal estrogen or placebo patches 0.1mg were randomly administered concurrent with the initiation of sertraline treatment. The 21 item Hamilton Depression Rating Scale (HDRS-21) was administered to all patients at baseline and weekly thereafter. RESULTS: Both groups showed a similar significant reduction in HDRS-21 scores by the end of the study. There was no significant difference between the two treatment groups at the end of the 10-week trial, but the women receiving sertraline with ET showed significantly greater early improvement (weeks 2-4) compared to the women receiving sertraline with placebo. CONCLUSIONS: Sertraline is an effective antidepressant for postmenopausal women with MDD. ET does not alter the response rate to antidepressant therapy however ET may play a role in accelerating the antidepressant response.     

The relationship between plasma serotonin and kynurenine pathway metabolite levels and the treatment response to escitalopram and desvenlafaxine

IntroductionThe response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels.MethodsThe levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤7.ResultsResponse to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047).ConclusionsIn MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.     

Brain activation predicts treatment improvement in patients with major depressive disorder

Major depressive disorder (MDD) is associated with alterations in brain function that might be useful for therapy evaluation. The current study aimed to identify predictors for therapy improvement and to track functional brain changes during therapy. Twenty-one drug-free patients with MDD underwent functional MRI twice during performance of an emotional perception task: once before and once after 4 weeks of antidepressant treatment (mirtazapine or venlafaxine). Twelve healthy controls were investigated once with the same methods. A significant difference between groups was a relative greater activation of the right dorsolateral prefrontal cortex (dlPFC) in the patients vs. controls. Before treatment, patients responding better to pharmacological treatment showed greater activation in the dorsomedial PFC (dmPFC), posterior cingulate cortex (pCC) and superior frontal gyrus (SFG) when viewing of negative emotional pictures was compared with the resting condition. Activations in the caudate nucleus and insula contrasted for emotional compared to neutral stimuli were also associated with successful treatment. Responders had also significantly higher levels of activation, compared to non-responders, in a range of other brain regions. Brain activation related to treatment success might be related to altered self-referential processes and a differential response to external emotional stimuli, suggesting differences in the processing of emotionally salient stimuli between those who are likely to respond to pharmacological treatment and those who will not. The present investigation suggests the pCC, dmPFC, SFG, caudate nucleus and insula may have a key role as a biological marker for treatment response and predictor for therapeutic success.     

Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder

The purpose of the present study was to determine if a 5-HT6 receptor polymorphism is associated with antidepressant treatment response in major depressive disorder (MDD). Ninety-one patients with MDD, compared with 127 normal control subjects, were evaluated after an 8-week treatment period. An association analysis revealed no differences in genotype and allele distribution between patients with MDD and normal control subjects. However, there were significant differences in the treatment response in some Hamilton Depression Rating Scale (HAM-D) scores (sleep, activity, somatic anxiety, and total) between genotypes. Moreover, the heterozygote group (CT genotype) had significantly better treatment response than the homozygote group (CC + TT genotypes), especially in the somatic-anxiety subcategory and the total score of HAM-D. These findings imply that a 5-HT6 receptor polymorphism (C267T) is associated with treatment response in MDD.     

An Investigation of Medial Temporal Lobe Changes and Cognition Following Antidepressant Response: A Prospective rTMS Study

BackgroundMajor depressive disorder (MDD) is often resistant to treatment with standard approaches. Repetitive transcranial magnetic stimulation (rTMS) is a new treatment that has proven antidepressant efficacy in treatment resistant MDD (TRD). Preliminary evidence also raises the possibility of rTMS enhancing neuronal plasticity; with demonstrated increases in serum levels of brain derived neurotrophic factor (BDNF) found. This is of most relevance to volumetric reductions associated with MDD, particularly in the hippocampus and related structures. Extensive preclinical literature suggests that hippocampal volume reductions from MDD induced suppression of adult neurogenesis can be reversed by different types of classical antidepressant treatments which increase expression of BDNF.ObjectiveThe aims of this study were to investigate whether antidepressant response to rTMS has similar therapeutic potential as antidepressant pharmacotherapy in promoting neurogenesis in the HC and surrounding structures and facilitating related neurocognitive improvements.MethodsMagnetic resonance imaging and neurocognitive assessments were conducted on 29 patients prior to rTMS treatment (baseline) and at three months post baseline (endpoint).ResultsOver time, antidepressant response was associated with a near significant increase in left amygdala volume (6.58%), whilst treatment non-responders showed significant declines in left hippocampus volumes (?2.64%) from baseline. Functionally, there was no cognitive deterioration following rTMS treatment. The results are limited, however, by sample size.ConclusionsThese preliminary findings suggest that rTMS may promote neurogenesis or other effects that favour neuronal plasticity and may also be neuroprotective for patients with TRD but these findings need replication in a larger sample.     

The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment

Neurotrophic factors are critical regulators of the formation and plasticity of neuronal networks. Brain-derived neurotrophic factor (BDNF) is abundant in the brain and periphery, and is found in both human serum and plasma. Animal studies have demonstrated that stress reduces BDNF expression or activity in the hippocampus and that this reduction can be prevented by treatment with antidepressant drugs. A similar change in BDNF activity occurs in the brain of patients with major depression disorder (MDD). Recently, clinical studies have indicated that serum or plasma BDNF levels are decreased in untreated MDD patients. Antidepressant treatment for at least four weeks can restore the decreased BDNF function up to the normal value. Therefore, MDD is associated with impaired neuronal plasticity. Suicidal behavior can be a consequence of severe impaired neuronal plasticity in the brain. Antidepressant treatment promotes increased BDNF activity as well as several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation. BDNF could also play an important role in the modulation of neuronal networks. Such a neuronal plastic change can positively influence mood or recover depressed mood. These alterations of BDNF levels or neuronal plasticity in MDD patients before and after antidepressant treatment can be measured through the examination of serum or plasma BDNF concentrations. BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression.     

Plasma brain-derived neurotrophic factor as a peripheral marker for the action mechanism of antidepressants

Numerous studies have demonstrated that depression is associated with a decreased expression of brain-derived neurotrophic factor (BDNF). BDNF shows antidepressant-like effects in animal models. Therefore, we tested the hypothesis that BDNF might be a peripheral marker for the mechanism of action of antidepressant agents in humans. Thirty-two patients meeting the DSM-IV criteria for major depressive disorder and 50 normal control subjects were recruited for this study. Plasma BDNF levels and Hamilton Depression Rating Scales were measured at baseline and 6 weeks after antidepressant administration. At baseline, the mean plasma BDNF level was lower in the depressive patients (698.1 +/- 537.7 pg/ml) than in the control subjects (830.7 +/- 624.8 pg/ml), although the difference was not statistically significant (p = 0.33). The plasma BDNF levels in depressive patients significantly increased from 698.1 +/- 537.7 to 1,028.9 +/- 744.5 after 6 weeks of antidepressant treatment (p = 0.01). Moreover, plasma BDNF levels were significantly increased after 6 weeks of treatment in the responder group, while there was no statistically significant change in the unresponsive group. These results suggest that the therapeutic response after antidepressant administration might be attributable to the increase in BDNF levels. BDNF may play a critical role in the action mechanism of antidepressant drugs. Further studies with a larger number of subjects are needed to verify these findings.