Reduced serum VGF levels were reversed by antidepressant treatment in depressed patients

Objectives: VGF, a non-acronymic neuropeptide, is important in the pathogenesis of major depressive disorder (MDD) and in the functioning and efficacy of some antidepressant drugs. In this study we assessed whether serum VGF levels change in MDD patients and if antidepressant treatments can restore these changes.

Methods: We measured serum VGF concentrations using sandwich ELISA in drug-free MDD patients before treatment began (n?=?26) and at 8 weeks after antidepressant treatment (n?=?26) with escitalopram and duloxetine, two common antidepressants. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS).

Results: VGF serum levels were significantly lower in MDD patients compared to controls (P?=?.002), even after controlling for the effects of age and education (P?=?.037), and they were reversed by 8 weeks of drug treatment (P < .0001). Both escitalopram and duloxetine restored the decreased serum VGF levels (P?P?=?.879).

Conclusions: The results suggest that VGF may be implicated in the pathophysiology of MDD and in the mechanisms underlying the action of antidepressants, and serum VGF may be regarded as a trait parameter for MDD.     

Usefulness of repetitive transcranial magnetic stimulation as a maintenance treatment in patients with major depression

Objectives: To investigate the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS), venlafaxine or a combination of both treatments as a maintenance treatment in patients with treatment-resistant depression (TRD).

Methods: In a three-arm open-label study, 66 patients, including 45 remitters, who responded to rTMS (n?=?25), venlafaxine (n?=?22), or a combination of both treatments (n?=?19) continued to receive the treatment that led to a response as a maintenance treatment over 12 months. Maintenance rTMS was administered twice per week for 1 month, once per week for 2 months, and once every 2 weeks for 9 months. Venlafaxine was maintained at the dose that induced a clinical response (150 or 225?mg/day).

Results: After the 12-month follow-up, the rates of remitters (HDRS?2?=^?1.25; P?=?.3). The rates of patients who not relapsed (HDRS?2?=^?0.33; P?=?.8): 40.0% in the rTMS group, 45.1% in the venlafaxine group and 36.9% in the combination group.

Conclusions: The three maintenance approaches exhibited similar efficacies in relapse prevention and the maintenance of remission in patients with TRD.     

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance–related processes may be involved in several phenotypes, including the TRD.     

An Evaluation of the Clinical and Economic Burden Among Older Adult Medicare-Covered Beneficiaries With Treatment-Resistant Depression

ObjectiveTo compare the clinical and economic burden of treatment-resistant depression (TRD) among older adult patients with major depressive disorder (MDD) to non-TRD MDD and non-MDD patients.MethodsRetrospective cohort study using 5% Medicare data (January 1, 2012–December 31, 2015) for MDD patients aged ≥65 years who were defined as TRD if they received ≥2 antidepressant treatments in the current episode. MDD patients not meeting TRD criteria were deemed non-TRD MDD; those without an MDD diagnosis were categorized as non-MDD. All were required to have continuous health plan enrollment for ≥6 months pre- and ≥12 months postindex date (index: first antidepressant claim/random [non-MDD]). Three cohorts were matched, and generalized linear and Cox proportional hazards models were used to compare medication use, healthcare resource utilization, costs, and risks of initial hospitalization and readmission ≤30 days postdischarge from initial hospitalization.ResultsAfter matching, 178 patients from each cohort were analyzed. During 12 months of follow-up, TRD patients had higher use of different antidepressants and antipsychotics, higher inpatient and emergency room visits, longer inpatient stays, and higher total healthcare costs ($24,543 versus $16,059, $8,058) than non-TRD MDD and non-MDD cohorts, respectively (all p <0.05). Risk of initial hospitalization was higher in the TRD (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 2.08–6.23) and non-TRD MDD cohorts (HR = 1.82, 95% CI = 1.02–3.25) than the non-MDD cohort.ConclusionsThe burden of MDD among older adult Medicare beneficiaries is substantial, and even greater among those with TRD compared to non-TRD MDD, demonstrating the need for more effective treatments than those currently available.     

Orexin/hypocretin receptor,Orx1, gene variants are associated with major depressive disorder

Objective: Orexins (hypocretins) are neuropeptides expressed in hypothalamic neurons and have regulatory roles in feeding/drinking behaviours, endocrine functions and sleep/wakefulness state. Major depressive disorder (MDD) is a major mood disorder and neurotransmitter dysfunction in hypothalamic neurons may have roles in its formation. Hence, we conducted experiments to determine whether orexin receptor 1 and 2 (Orx₁, Orx₂) genes were associated with MDD development.

Methods: Seventy-five MDD patients and 87 healthy controls were enrolled for the study. Genotyping was carried out with real-time polymerase chain reaction (RT-PCR). Hamilton Rating-Scale for Depression (HRSD) and Beck Depression Inventory (BDI) were utilized to evaluate depressive symptom severity.

Results: A significant relation was found in genotype frequencies of Orx₁ rs10914456 and rs2271933 variants between MDD patients and controls (p?=?.009, p?=?.006). Rs10914456?CC genotype increased MDD risk 3.57 times more than carrying other genotypes (p?=?.008, OR =3.57;95% CI: 1.39–9.14). However, no association was observed in Orx₂ rs2653349 genotypes for MDD development (p?>?.05). Although statistically not significant, HRSD scores were diminished in MDD subjects carrying rs10914456?CC variants when compared with CT and TT variants (p?=?.069). Conclusion. This study suggests that, Orx₁ rs10914456 and rs2271933 can be associated with MDD development. Hence, Orx₁ rs10914456 variants may affect depressive symptom severity.     

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.     

Hypoesthesia in generalised anxiety disorder and major depression disorder

Abstract

Objective: The determination of soft signs can be a conducive practice to understand the differential etiology between depression and anxiety. This study aims at examining malleolar hypoesthesia role in distinguishing between patients with generalised anxiety disorder (GAD) and major depression disorder (MDD).

Methods: This study examines the presence of malleolar hypoesthesia in patients with GAD (n?=?47) compared to patients with MDD (n?=?48) and healthy individuals (controls; n?=?99). The Wartenberg wheel, a medical device for neurological use, was employed to determine the presence of hypoesthesia on both sides of the ankles.

Results: The data revealed: i) MDD patients showed higher hypoesthesia than GAD patients (p?=?.008), ii) participants with hypoesthesia had higher anxiety and depression scores than participants without hypoesthesia (all p?<?.001) and iii) logistic regression model indicated that hypoesthesia can be a predictor of MDD relative to GAD diagnosis (Odds Ratio: 17.43 (1.40–217.09; p?=?.026)).

Conclusions: Malleolar hypoesthesia was higher in MDD than GAD. The detection of hypoesthesia may help to investigate the differential etiology between MDD and GAD diagnosis.     

IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk

Background: Considering current scientific evidence about the significant role of chronic low grade inflammation in the physiopathology of schizophrenia, it has been hypothesized that changes in pro-inflammatory cytokines such as interferon gamma may have a significant role in the predisposition to schizophrenia.

Aim: This study focuses on identifying whether the functional polymorphism of interferon gamma receptor 2 (IFNGR2) is a risk factor for the development of schizophrenia.

Methods: This study was conducted by the RFLP-PCR on a Tunisian population composed of 225 patients with different sub-types of schizophrenia and 166 controls.

Results: The IFNGR2 (Q64R) polymorphism analysis showed higher frequencies of minor homozygous genotype (RR) and allele (R) in all patients compared to controls (21.8% vs 10.2%; p?=?.006, OR?=?2.54) and (44% vs 34.9%; p?=?.01; OR?=?1.46), respectively. This correlation was confirmed only for males. This study also noted a significant increase of the mutated homozygous (RR) genotype and (R) allele frequencies of IFNGR2 in paranoid schizophrenics compared to controls (31.4% vs 10.2%; p?=?.001; OR?=?3.34 and 47.2% vs 34.9%; p?=?.009; OR?=?1.66, respectively). This increase remains significant after using binary logistic regression to eliminate confounding factors such as age and sex. Additionally, carriers of RR genotype have significant lower scores on the Scale of Assessment of Positive (SAPS) and negative (SANS) symptoms comparatively to the carrier of the QQ?+?QR genotypes, suggesting that the R recessive allele carriers could have milder symptoms.

Conclusion: The IFNGR2Q64R polymorphism is correlated with male sex and paranoid schizophrenia. It is suggested that a chronic neuroinflammation may predispose to the paranoid schizophrenia development in men.     

Interleukin 6-174G>C polymorphism and risk of aneurysmal subarachnoid hemorrhage: case-control study and meta-analysis

Pera J, Dziedzic T, Adamski M, Jagiella J, Krupa M, Moskala M, Szczudlik A, Slowik A. Interleukin 6–174G>C polymorphism and risk of aneurysmal subarachnoid hemorrhage: case–control study and meta‐analysis.
Acta Neurol Scand: 2012: 125: 111–115.
© 2011 John Wiley & Sons A/S. Objectives – Vascular inflammation contributes to the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH). Interleukin 6 (IL6) is a proinflammatory cytokine involved in many vascular pathologies. Two studies analyzing an association of the functional IL6 gene –174G>C promoter polymorphism with aSAH provided inconsistent results. The aim of this study was to investigate whether this IL6 polymorphism is associated with aSAH in a Polish population. Material and methods – We genotyped 276 aSAH patients and 581 unrelated control subjects. All were of Caucasian origin. In addition, a meta‐analysis combining results of the current and previously published studies was conducted. Results – The distribution of IL6 genotypes and alleles did not differ significantly between aSAH (GG – 29.7%, GC – 50.0%, CC – 20.2%, G – 54.7%) and control subjects (GG – 32.0%, GC – 47.3%, CC – 20.7%, G – 44.3%). In the meta‐analysis, the IL6–174G>C polymorphism was not associated with aSAH risk either. Conclusions – We failed to find an association between the IL6 ‐174G>C polymorphism and aSAH in analyzed European populations.     

Smaller hippocampal volumes predict lower antidepressant response/remission rates in depressed patients: A meta-analysis

Objectives: Whether hippocampal volume predicts response and/or remission after antidepressant treatment of major depressive episodes (MDE) in major depressive disorder (MDD) remains unclear. We meta-analysed prospective studies comparing baseline hippocampal volume in patients with or without response/remission after antidepressant treatment.

Methods: Pubmed, Embase and Google Scholar were searched for studies of patients with current MDE in MDD, with hippocampal volume assessments at baseline, initiation of antidepressant drug treatment, and prospective assessment of response/remission after treatment.

Results: Six studies (374 patients), of which two were positive and four negative, were meta-analysed. Compared to responders/remitters, patients who failed to achieve response/remission had smaller total hippocampus volumes at baseline (mean volume difference?=?260?mm³, 95% CI [93; 427], P?=?0.002). These results remained significant in patients under 60 years of age (P?=?0.02), in those over 60 years old (P?=?0.04), and for right (P?=?0.006) and left (P?=?0.02) hippocampi. The probability of non-response/non-remission was 68.6% for patients with a total hippocampal volume at least 10% lower than the average, and 47.1% for patients with a total hippocampal volume 10% higher than the average.

Conclusions: In depressed patients treated with antidepressant drugs, smaller hippocampal volumes predict lower response/remission rates.