Mismatch negativity in treatment-resistant depression and borderline personality disorder

Objective

Cognitive dysfunctions, such as attentional impairment, are central features of both treatment-resistant depression (TRD) and borderline personality disorder (BPD). The treatment failure of TRD due to its comorbidity with BPD is debated in the literature. The mismatch negativity (MMN) of the event-related potentials provides an objective marker of involuntary stimulus selective processing, which might help shed light on this issue and provide an avenue for investigating a possible endophenotypic marker for TRD.

Method

We investigated MMN in 22 patients with TRD, 19 with BPD, and 22 with TRD cormorbid with BPD (TRD + BPD), as well as in 32 healthy volunteers, by employing an acoustic frequency deviance paradigm. In addition, we measured the depressive mood using the Plutchik–van Praag (PVP) depression inventory.

Results

There was no significant between-group difference for the N1 latencies/amplitudes, both to the standard and deviant stimuli, and no significant between-group difference for MMN latencies. However, MMN amplitudes were higher in the TRD group than those in the other three groups. PVP scores were highest in TRD + BPD, then TRD, BPD patients, and lowest in healthy subjects. The higher MMN was not correlated with PVP score, nor with the duration of life-long depression, which can be considered as a neurophysiological marker for TRD.

Conclusion

An atypical lack of inhibition on the irrelevant stimuli or increased cortical neuronal activity, especially frontal area, or both, might be responsible for the finding.     

Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study.

BACKGROUND: The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established. METHODS: This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. RESULTS: The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD(24)) scores (average improvement, .45 points [SE = .05] per month (p < .001). At exit, HRSD(24) response rate was 27.2% (55/202); remission rate (HRSD(24) < or = 9) was 15.8% (32/202). Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events. CONCLUSIONS: These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS.     

Renin-angiotensin-system gene polymorphisms and depression

Given the abundance of the renin-angiotensin system (RAS) components in the brain, their importance in behavior and cognition, and the data that implicates them in the etiology and treatment of depression, it is possible that those RAS gene polymorphisms associated with increased RAS activity may also be associated with depression. The frequencies of common polymorphisms of genes encoding for components of the RAS, namely angiotensinogen (M235T), angiotensin converting enzyme (ACE) (insertion, I; deletion, D), angiotensin receptor type I (A1166C), and angiotensin receptor type II (C3123A) were determined in DNA extracted from buccal cells from a Lebanese population of 132 depressed patients and their first-degree relative case-controls. The angiotensin receptor type 1 (A1166C) CC genotype was significantly associated with depression (p=0.036). None of the other common RAS-associated polymorphisms were significantly associated. The results support the hypothesis that increased RAS activity may increase relative risk of depression in that the angiotensin receptor type 1 (A1166C) CC genotype is associated with increased responsiveness to angiotensin II.     

Disrupted regional homogeneity in treatment-resistant depression: a resting-state fMRI study

Background

Using a newly developed regional homogeneity (ReHo) approach, we were to explore the features of brain activity in patients with treatment-resistant depression (TRD) in resting state, and further to examine the relationship between abnormal brain activity in TRD patients and specific symptom factors derived from ratings on the Hamilton Rating Scale for Depression (HRSD).

Methods

24 patients with TRD and 19 gender-, age-, and education-matched healthy subjects participated in the fMRI scans.

Results

1.

Compared with healthy controls, decreased ReHo were found in TRD patients in the left insula, superior temporal gyrus, inferior frontal gyrus, lingual gyrus and cerebellum anterior lobe (culmen) (p < 0.05, corrected).

2.

Compared with healthy controls, increased ReHo were found in the left superior temporal gyrus, cerebellum posterior lobe (tuber), cerebellum anterior lobe (culmen), the right cerebellar tonsil and bilateral fusiform gyrus (p < 0.05, corrected).

3.

There was no correlation between the ReHo values in any brain region detected in our study and the patients' age, years of education, illness duration, HRSD total score and its symptom factors.

Limitation

The influence of antidepressants to the brain activity in TRD patients was not fully eliminated.

Conclusions

The pathogenesis of TRD may be attributed to abnormal neural activity in multiple brain regions.     

Altered white matter integrity of forebrain in treatment-resistant depression: a diffusion tensor imaging study with tract-based spatial statistics

Background

The association between alterations of the white matter (WM) integrity in brain regions and mood dysregulation has been reported in major depressive disorder (MDD). However, there has never been a neuroimaging study in patients who have treatment-resistant depression (TRD) and are in a current treatment-resistant state. In the present study, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) method to investigate the WM integrity of different brain regions in patients who had TRD and were in a current treatment-resistant state.

Methods

Twenty-three patients with TRD and Hamilton Rating Scale total score of ≥ 18 and 19 healthy controls matched with age, gender, and education level to patients were scanned with DTI. Thirty 4 mm thick, no gap, contiguous axial slices were acquired and fractional anisotropy (FA) images were generated for each participant. An automated TBSS approach was used to analyze the data.

Results

Voxel-wise statistics revealed that patients with TRD had lower FA values in the right anterior limb of internal capsule, the body of corpus callosum, and bilateral external capsule compared to healthy subjects. Patients with TRD did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain region and patients' demographics and the severity of illness.

Conclusions

Our findings suggest the abnormalities of the WM integrity of neuronal tracts connecting cortical and subcortical nuclei and two brain hemispheres may play a key role in the pathogenesis of TRD.     

Alterations of the amplitude of low-frequency fluctuations in treatment-resistant and treatment-response depression: A resting-state fMRI study

Background

Patients with treatment-resistant depression (TRD) and those with treatment-response depression (TSD) respond to antidepressants differently and previous studies have commonly reported different brain networks in resistant and nonresistant patients. Using the amplitude of low-frequency fluctuations (ALFF) approach, we explored ALFF values of the brain regions in TRD and TSD patients at resting state to test the hypothesis of the different brain networks in TRD and TSD patients.

Methods

Eighteen TRD patients, 17 TSD patients and 17 gender-, age-, and education-matched healthy subjects participated in the resting-state fMRI scans.

Results

There are widespread differences in ALFF values among TRD patients, TSD patients and healthy subjects throughout the cerebellum, the visual recognition circuit (middle temporal gyrus, middle/inferior occipital gyrus and fusiform), the hate circuit (putamen), the default circuit (ACC and medial frontal gyrus) and the risk/action circuit (inferior frontal gyrus). The differences in brain circuits between the TRD and TSD patients are mainly in the cerebellum, the visual recognition circuit and the default circuit.

Conclusions

The affected brain circuits of TRD patients might be partly different from those of TSD patients.     

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.     

Hopelessness, a potential endophenotpye for suicidal behavior, is influenced by TPH2 gene variants

Objectives

Hopelessness is one of the strongest risk factors for suicidal behavior but relevant genetic studies are poorly available. Tryptophan hydroxylase (TPH) is widely considered to be a good candidate for genetic association studies on depression and suicide, however, investigations on these complex, multifactorial phenotypes have resulted in conflicting data. We hypothesized that hopelessness could be a mediating phenotype between TPH2 gene, depression and suicidal behavior.

Methods

Depressive phenotype and suicidal risk were investigated of 760 individuals from general population by Zung Self Rating Depression Scale (ZDS), Beck's Hopelessness Scale (BHS) and a detailed background questionnaire. All participants' DNA samples were genotyped for 7 tag SNPs in TPH2 gene. Generalized linear models were performed for single marker association studies and p-values were corrected by Bonferroni criteria. In haplotype analyses score tests were used and permutated p-values were computed.

Results

Four SNPs of TPH2 gene showed association with hopelessness but only rs6582078 had a significant effect on the BHS scores after Bonferroni's correction; GG individuals had significantly higher BHS scores, while GT and TT had intermediate and lower BHS scores respectively (p = 0.0047). Compared with other genotypes, homozygous GG individuals also had almost three times greater estimated suicidal risk, as did carriers of the AA genotype of rs6582078 (OR = 2.87; p = 0.005) and also of rs1352250 (OR = 2.86; p = 0.006). A risk and a protective haplotype of TPH2 gene were also identified in association with hopelessness. ZDS scores have not shown any association with TPH2 gene.

Conclusions

We found that hopelessness, with its allied increased suicidal risk was strongly associated with TPH2 gene variants in multiple tests. These findings suggest that TPH2 gene confers risk for suicidal behavior while hopelessness can be a potential endophenotype for suicidal vulnerability.     

Periventricular white matter hyperintensities as predictors of suicide attempts in bipolar disorders and unipolar depression

The aim of this study was to evaluate whether deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVH) are associated with suicidal behavior in patients with major affective disorders. Subjects were 99 consecutively admitted inpatients (42 men; 57 women; mean age: 46.5 years [SD=15.2; Min./Max.=19/79]) with a diagnosis of major affective disorder (bipolar disorder type I, bipolar disorder type-II and unipolar major depressive disorder). 44.4% of the participants had made at least one previous suicide attempt. T2-weighted brain magnetic resonance images were rated for the presence and extension of WMH using the modified Fazekas scale. Patients were interviewed for clinical data on average 5 days after admission. Bivariate analyses, corrected for multiple-testing, and logistic regression analysis were used to test the association between suicide attempts and clinical variables. Attempters and nonattempters differed only in the presence of PVH--the former were more likely to have PVH. The logistic regression indicated that the presence of PVH was robustly associated with suicidal behaviors after controlling for age (OR: 8.08). In conclusion, neuroimaging measures may be markers of risk for suicidal attempts in patients with major affective disorders.     

Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat

A substantial number of patients with major depressive disorder (MDD) do not respond adequately to current antidepressant pharmacological treatments, which are all more or less based on a gradually increased enhancement of monoaminergic neurotransmission. Although a functional deficiency in monoaminergic neurotransmission may contribute to MDD, the etiology and pathophysiology are far from clarified. Recent studies suggest that inflammatory processes may contribute, since increased levels of pro-inflammatory cytokines and prostaglandin E(2) (PGE(2)) have repeatedly been observed in a subset of patients suffering from MDD. Interestingly, adjunct treatment with the anti-inflammatory drug celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor which blocks the PGE(2)-production, has shown to enhance the efficacy of both reboxetine, a selective noradrenaline reuptake inhibitor, as well as fluoxetine, a selective serotonin reuptake inhibitor, in treatment-resistant depression. To examine the neurobiological underpinnings to the clinical observations, we here studied the acute effects of a combined treatment with celecoxib and reboxetine on noradrenaline and dopamine output, as well as celecoxib and fluoxetine on 5-HT output in the medial prefrontal cortex, using in vivo microdialysis in awake freely moving rats. Celecoxib significantly potentiated the effects of reboxetine and fluoxetine on cortical noradrenaline and 5-HT output, respectively, but not the reboxetine-induced dopamine output. Moreover, celecoxib, when given alone, enhanced 5-HT output. These findings provide, in principle, novel experimental support for the clinical utility of combined treatment with antidepressant and anti-inflammatory drugs, such as COX-2 inhibitors, in MDD.     

A monoamine oxidase B gene variant and short-term antidepressant treatment response

Genetic differences among patients suffering from Major Depression are likely to contribute to interindividual differences in medication treatment response. Thus, the identification of gene variants affecting drug response is needed in order to be able to predict response to psychopharmacological drugs. This study analyzed a possible association of the common A644G single nucleotide polymorphism (SNP) within intron 13 of the monoamine oxidase B (MAOB) gene with antidepressant treatment response. The study population consisted of n = 102 patients with major depression (criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; DSM-IV) participating in a randomized double-blind controlled clinical trial, conducted at 50 centers in Germany, comparing the efficacy of mirtazapine and paroxetine during 6 weeks of treatment. Overall, female patients homozygous for the A-allele had a significantly faster and more pronounced antidepressant treatment response than AG/GG-carriers. In paroxetine-treated females these differences remained statistically significant. In mirtazapine-treated females homozygous for the A-allele compared to AG/GG-carriers, HAMD-17 scores during the study period were constantly and markedly lower, but not statistically different. In males, we found no association between the MAOB A644G intron 13 SNP and antidepressant treatment response. Our data provide first suggestive evidence that the MAOB A644G SNP is involved in the outcome of treatment with mirtazapine or paroxetine in females with major depression. To confirm the role of the MAOB A644G gene variant in antidepressant treatment response, independent replications are needed. If replicated, the MAOB A644G polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.     

Acute and subsequent continuation electroconvulsive therapy elevates serum BDNF levels in patients with major depression

IntroductionThe induction of brain-derived neurotrophic factor (BDNF) release and subsequent restoration of neuroplastic homeostasis may underlie the effects of electroconvulsive therapy (ECT).ObjectivesWe aimed to assess serum and plasma BDNF levels during the course of acute ECT, as well as before and after subsequent continuation ECT, in patients with depression.MethodsWe included 24 patients with major depressive disorder (mean age ± SD: 54.5 ± 13.7; f/m: 17/7; baseline 17-item Hamilton Depression Rating Scale score of 26.79 ± 4.01). Serum and plasma BDNF (sBDNF, pBDNF) levels were assessed at nine time-points before, during, and after acute ECT series. Data were analysed using linear regression and linear mixed models, which were adjusted for multiple comparisons via Bonferroni correction. Five patients received continuation ECT subsequent to the acute ECT series. In these patients, BDNF levels were assessed before and after each two continuation ECT sessions using Wilcoxon signed-rank tests.ResultsRelative to baseline (mean ng/ml ±SD: 24.68 ± 14.40), sBDNF levels were significantly higher 1 day (33.04 ± 14.11, p = 0.013, corrected), 1 week (37.03 ± 10.29, p < 0.001, corrected), and 1 month (41.05 ± 10.67, p = 0.008, corrected) after the final ECT session, while pBDNF levels did not significantly differ (p > 0.1). Furthermore, our results indicated that sBDNF levels increased after each continuation ECT session. There was no significant association between sBDNF levels and clinical parameters or treatment response.ConclusionThe absence of an association between changes in sBDNF levels and depressive symptoms challenges the proposed concept of sBDNF/pBDNF as key markers of the effects of ECT.