First-episode Major Depressive Disorder Research Articles

Relationship between initial self-perceived depressive symptoms and disease severity in working patients with first-onset major depressive disorder.

The severity of major depressive disorder (MDD), which is related to the depressive symptoms, is a predictor of clinical outcomes and may be used to determine the appropriate treatment. However, there is a lack of systematic research on the relationship between early depressive symptoms and MDD severity. This study aimed to clarify the association between initial depressive symptoms and MDD severity in working patients. We assessed 118 patients aged over 20 years who visited the Neuropsychiatry Department of the Osaka City University Hospital following their first episode of MDD. Logistic regression analyses were performed to estimate the odds ratios (OR) with 95% confidence intervals (CI) for the associations between age, gender, marital status, working hours, and initial self-perceived depressive symptoms and MDD severity. Age and working hours were analyzed as continuous variables, and gender (man, woman), marital status (married, single) and severity (mild to moderate MDD, severe to very severe MDD) were analyzed as categorical variables. The most common initial self-perceived symptom was "depressed mood," followed by "fatigue or loss of energy nearly every day." The univariate analysis found no association between age, gender, marital status, or working hours and MDD severity. Initial self-perceived non-somatic symptoms were associated with increased odds of having severe MDD (odds ratio = 3.32, 95% confidence interval 1.46-7.58), and this association persisted in the adjusted model (odds ratio = 3.35, 95% confidence interval 1.47-7.60). Initial self-perceived non-somatic depressive symptoms are significantly associated with MDD severity at its first onset. Workplace support may lead to the early detection and treatment of working patients with non-somatic symptoms.

Dynamic Altered Amplitude of Low-Frequency Fluctuations in Patients With Major Depressive Disorder.

Background: Major depressive disorder (MDD) has demonstrated abnormalities of static intrinsic brain activity measured by amplitude of low-frequency fluctuation (ALFF). Recent studies regarding the resting-state functional magnetic resonance imaging (rs-fMRI) have found the brain activity is inherently dynamic over time. Little is known, however, regarding the temporal dynamics of local neural activity in MDD. Here, we investigated whether temporal dynamic changes in spontaneous neural activity are influenced by MDD.Methods: We recruited 81 first-episode, drug-naive MDD patients and 64 age-, gender-, and education-matched healthy controls who underwent rs-fMRI. A sliding-window approach was then adopted for the estimation of dynamic ALFF (dALFF), which was used to measure time-varying brain activity and then compared between the two groups. The relationship between altered dALFF variability and clinical variables in MDD patients was also analyzed.Results: MDD patients showed increased temporal variability (dALFF) mainly focused on the bilateral thalamus, the bilateral superior frontal gyrus, the right middle frontal gyrus, the bilateral cerebellum posterior lobe, and the vermis. Furthermore, increased dALFF variability values in the right thalamus and right cerebellum posterior lobe were positively correlated with MDD symptom severity.Conclusions: The overall results suggest that altered temporal variability in corticocerebellar–thalamic–cortical circuit (CCTCC), involved in emotional, executive, and cognitive, is associated with drug-naive, first-episode MDD patients. Moreover, our study highlights the vital role of abnormal dynamic brain activity in the cerebellar hemisphere associated with CCTCC in MDD patients. These findings may provide novel insights into the pathophysiological mechanisms of MDD.

Prospective study on microstructure in medication-naïve adolescents with first-episode major depressive disorder

Background: Major depressive disorder (MDD) is one of the most prevalent mental disorders during adolescence, and early diagnosis and treatment are important. We aimed to characterize the microstructure of the brain in medication-naïve adolescents with first-episode MDD. Methods: Patients with MDD (N = 31) and healthy controls (N = 27) participated in this study and severity of depressive symptoms, duration of untreated depressive episode, demographic data, and diffuse tensor imaging data were collected. A comparative analysis of patients and healthy controls was performed, and the effect of medication on the brain`s integrity was investigated through comparison before and after 3 months of treatment in the patient group. Tract-based spatial statistics was used for diffusion tensor image analysis. Results: In the patient group, functional anisotropy (FA) values were significantly higher at the genu of the corpus callosum, body of the corpus callosum, and right anterior corona radiata than in healthy controls. After 3 months of treatment, FA values were significantly decreased in the left anterior limb of the internal capsule, left posterior limb of the internal capsule, and left superior longitudinal fasciculus. Limitations: The sample size is relatively small and 3-month treatment period was relatively short. Conclusion: FA values of patients with MDD were increased compared to healthy controls and decreased after treatment. These results suggested that pharmacological treatments in the early stages of MDD might restore the brain`s integrity.

Sex differences in the association between suicide attempts and glucose disturbances in first-episode and drug naive patients with major depressive disorder

BackgroundGlucose metabolism is related to depression, but the relationship between blood glucose and suicide attempts in patients with major depressive disorder (MDD) remains unclear. This large-scale sample explores the relationship between suicide attempts and fasting blood glucose, in addition to sex differences in first-episode and drug naive (FEDN) MDD patients. Methods1718 FEDN MDD patients diagnosed for the first time were recruited, and their demographic data, clinical data, and blood glucose indicators were collected. 17-item Hamilton Depression Rating Scale (HAMD), 14-item Hamilton Anxiety Rating Scale (HAMA), and positive subscale of the Positive and Negative Syndrome Scale (PANSS) were used to assess their depression, anxiety and psychotic symptoms, respectively. ResultsThe depression, anxiety, psychotic symptoms and blood sugar levels of the suicide attempt group were higher than those of the non-suicide attempt group. Correlation analysis showed that blood glucose was significantly associated with suicide attempts in male and female patients. While binary logistic regression showed that blood glucose levels were significantly associated with suicide attempts in male patients, it showed that suicide attempts were not significantly associated with blood glucose levels in female patients. LimitationsThe main limitations are cross-sectional design and inability to control selection bias. ConclusionsIn male MDD patients, fasting blood glucose level is a potential biomarker of suicide attempt, which deserves attention to avoid suicide risk. However, in female patients, fasting blood glucose has no significant correlation to suicide attempts.

Anomalous functional connectivity within the default-mode network in treatment-naive patients possessing first-episode major depressive disorder.

Background and Objective:Previous studies have shown that the default-mode network (DMN) has a substantial role in patients with major depressive disorder (MDD). However, there is a shortage of information regarding variations in the functional connectivity (FC) of the DMN of treatment-naive patients with first-episode MDD. The present study aims to explore the FC of the DMN in such patients.Methods:The study population consisted of 33 patients and 35 controls, paired regarding age, gender, education level, and health condition. Depression severity was assessed through the Hamilton Depression Scale (HAM-D), and subjects underwent evaluation during the resting-state through functional magnetic resonance imaging (rs-fMRI). To assess the result, we used FC and ICA. We used Spearman's correlation test to detect potential correlations between anomalous FC and severity of HAM-D scores.Results:We have found a decreased FC in the left medial orbitofrontal gyrus (MOFG) and right marginal gyrus (SMG) in depressive patients compared to controls. There was a negative correlation between abnormal FC in the right SMG and HAM-D scores. We have not found any increase in FC of the DMN in treatment-naive, first-episode of MDD patients.Conclusions:Our study provided evidence of a negative correlation between abnormal FC in the DMN and severity of depression symptoms measured by HAM-D in treatment-naive MDD patients. This finding could shed some light on the relevance of DMN for understanding the pathophysiology of cognitive impairment in MDD.

Serum Lipid Levels and Suicide Attempts Within 2 Weeks in Patients With Major Depressive Disorder: Is There a Relationship?

The potential correlation between serum lipid profiles and suicidal tendencies has been previously reported, however, it is unclear whether serum lipid profiles have definite relevance to recently attempted suicides in individuals suffering from major depressive disorder (MDD). In this study, the relationship between blood lipids and suicide attempts in first-episode MDD patients in research were used to examine whether there is a connection. The cross-sectional study recruited 580 patients at the time of their first episode, measuring up to the diagnostic standard of MDD. Baseline demographic, clinical data, and blood lipid level data were collected. Depression severity was measured with the Hamilton Depression Rating Scale (HAMD). Our results revealed that the level of TC may be identified as a promising and effective biomarker for first-episode MDD suicide risk, suggesting that screening of serum lipid profiles in depressive patients is essential for suicide prevention.

First-Episode Patients Report Cognitive Difficulties in Executive Functioning 1 Year After Initial Episode of Major Depressive Disorder

Objective: Major Depressive Disorder (MDD) is associated with cognitive impairment in general, and Executive Functioning (EF) in particular, even in remitted phase of the disorder, suggesting residual cognitive symptoms. The aim of the present study was to investigate self-reported EF 1 year after the first episode of MDD and to explore this in relation to depressive mood symptoms, remission and relapse.Method: The study included data from 24 patients and 23 healthy control subjects 1 year after the patients' initial first episode of MDD. All participants completed the Behavior Rating Inventory of Executive Functioning-Adult version (BRIEF-A), a standardized self-report measure of perceived EF in everyday life, measuring nine different EF. Total index scores for metacognitive functions, behavior/emotional regulation functions and a global EF score is also calculated.Results: The patient group in total, independent of symptom status, reported significantly lower EF in all indexes compared to the healthy controls 1 year after the initial episode. However, higher depressive mood symptom load correlated with self-reported difficulties in metacognitive functions and poor global EF scores. Regulatory control of behavior and emotional responses did not show such strong association with mood symptoms, but low self-report scores on this measure was associated with relapse during the first year after the initial episode.Conclusion: First-episode patients report significant lower executive functioning in everyday life compared to individually matched healthy controls, 1 year after onset, independent of symptom load. Residual cognitive symptoms seem to be evident and associated with risk of relapse and should be targeted in treatment and prevention of recurrence in MDD.

Severe sleep disturbance is associated with executive function impairment in patients with first-episode, treatment-na\xefve major depressive disorders

BackgroundSleep disturbance and executive function impairment are common in patients with major depressive disorder (MDD), though the relationship between the two remains unclear. We investigated this association in first-episode, treatment-naïve patients with MDD.MethodsWe analyzed data from 242 patients with MDD. We divided the patients into 2 groups based on sleep disturbance severity and compared the executive function odds ratios between the groups.ResultsA total of 121 pairs of patients were matched (age 39.4 ± 10.1, 70.2% female). After propensity score matching, the odds ratios for cognitive impairment in patients with MDD and severe sleep disturbance were 1.922 (1.068–3.459, P = 0.029, q = 0.044) in executive functioning; 2.023 (1.211–3.379, P = 0.007, q = 0.021) in executive shifting.ConclusionsSleep disturbance is associated with executive functioning impairment in first-episode, treatment-naïve patients with MDD. Severe sleep disturbance can be a marker and aid in recognizing executive function impairment in patients with first-episode treatment-naïve MDD. Severe sleep disturbance can be a potential modifiable factor to improve executive function in MDD, as well as an effective measurement to improve cognition for sleep symptom management that should be enforced at initial treatment of first-episode MDD. Further study is required to confirm our results.Trial registrationClinicalTrials.gov: NCT02023567; registration date: December 2013.

Inverse autonomic stress reactivity in depressed patients with and without prior history of depression

IntroductionThere is a considerable association between major depressive disorder (MDD) and cardiovascular disease, most possibly relying on abnormalities in the autonomic nervous system (ANS)-related cardiac reactivity, although the exact underlying pathophysiological pathway is unclear.ObjectivesThis study tends to shed some additional light on this background by investigating ANS reactivity in MDD with respect to previous depression history through an objective stress challenge paradigm.MethodsThe study assessed the effects of an overnight hypothalamus-pituitary-adrenal (HPA) axis stimulation with metyrapone (MET) on baseline ANS activity through linear and non-linear heart rate variability (HRV) measures in the morning of two continuous days in a group of 14 physically healthy, antidepressant-free patients with clinical, non-psychotic MDD, to investigate differences in autonomic reactivity with respect to prior MDD history.ResultsThe main findings of this study include statistically significant time x group interactions with respect to several HRV measures, suggesting substantial differences on autonomic reactivity between patients with and without depression history. Hereby, recurrent-episode MDD patients showed lower vagal activity, while first-episode MDD patients increased PNS activity after HPA axis stimulation.ConclusionsThese findings indicate that HPA axis stimulation in MDD patients leads to inverse vagal response according to MDD history. We suggest that chronic stress system overactivation, as found in MDD, might lead to a progressive inversion of the original stress response through HPA axis and ANS divergence over the course of a recurrent illness. HRV could, thus, represent a significant biomarker in MDD with temporal sensitivity.

The relationship between plasma cytokine levels and antidepressant response in patients with first-episode major depressive disorder

BackgroundCytokines are involved in the pathophysiology of major depressive disorder (MDD) and treatment response. Efforts have been made to identify inflammatory markers but results are often contradictory. The present study explored the plasma levels of multiple cytokines in first-episode MDD using a longitudinal design, with the aim to determine the involvement of cytokines in depression and identify the inflammatory markers. MethodFifty-four first-episode drug naïve MDD patients and 60 healthy controls (HCs) were enrolled in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered and blood samples were collected at baseline and four-week posttreatment in MDD group, while blood samples were only collected once in HC group. Plasma levels of nineteen cytokines were examined by a multiplexed flow cytometric assay. ResultsSixteen out of 19 cytokines levels in MDD group were significantly higher than those in HC group (all P < 0.05). After 4-week of antidepressant treatment, levels of the 14 cytokines elevated at baseline decreased to normal levels (all P < 0.05). Partial correlation showed that baseline level of interferon-inducible T cell alpha chemoattractant (ITAC) was negatively correlated with reduction in HAMD-17 score (r=−0.319, p=0.020), and multiple regression showed lower baseline ITAC level was associated with better treatment response (p = 0.020). LimitationThe sample size was relatively small. ConclusionA range of cytokines were abnormal in patients with first-episode drug naïve MDD and most of the cytokines could be normalized after antidepressant treatment. Furthermore, baseline ITAC level could be a predictive factor of antidepressant response.

Serotonergic receptor gene polymorphism and response to selective serotonin reuptake inhibitors in ethnic Malay patients with first episode of major depressive disorder.

The polymorphisms of the 5HTR1A and 5HTR2A receptor genes (rs6295C/G and rs6311G/A) have been evaluated for association with SSRI treatment outcome in various populations with different results. The present study was carried out to determine the association between genotypes of HTR1A-rs6295 and HTR2A-rs6311 with SSRI treatment outcome among the ethnic Malay patients diagnosed with first-episode major depressive disorder (MDD). The patients were recruited from four tertiary hospitals in the Klang Valley region of Malaysia. Predefined efficacy phenotypes based on 25% (partial early response) and 50% (clinical efficacy response) reduction in Montgomery Asberg Depression Rating Scale-self Rated score (MADRS-S) were adopted for assessment of treatment efficacy in this study. Self-reporting for adverse effects (AE) was documented using the Patient Rated Inventory of Side Effect (PRISE) after treatment with SSRI for up to 6 weeks. Adjusted binary logistic regression between genotypes of the polymorphism obtained using sequencing technique with the treatment outcome phenotypes was performed. The 142 patients recruited were made up of 96 females (67.6%) and 46 males (32.4%). Clinical efficacy and Partial early response phenotypes were not significantly associated with genotypes of HTR1A and HTR2A polymorphism. The GG genotype of HTR2A polymorphism has decreased odds for dizziness (CNS) and increased odds for poor concentration. The GA genotype increases the odd for excessive sweating, diarrhoea, constipation and blurred vision. The CC genotype of HTR1A-rs6295 decreases the odd for nausea/vomiting and increases the odd for anxiety. Thus, some genotypes of HTR1A and HTR2A polymorphism were associated with SSRI treatment outcomes in ethnic Malay MDD patients.

Cognitive Impairment in Adolescent Major Depressive Disorder With Nonsuicidal Self-Injury: Evidence Based on Multi-indicator ERPs.

The lifetime prevalence of major depressive disorder (MDD) in adolescents is reported to be as high as 20%; thus, MDD constitutes a significant social and public health burden. MDD is often associated with nonsuicidal self-injury (NSSI) behavior, but the contributing factors including cognitive function have not been investigated in detail. To this end, the present study evaluated cognitive impairment and psychosocial factors in associated with MDD with NSSI behavior. Eighteen and 21 drug-naïve patients with first-episode MDD with or without NSSI (NSSI+/– group) and 24 healthy control subjects (HC) were enrolled in the study. The Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Adolescent Self-injury Questionnaire, Beck Scale for Suicide Ideation–Chinese Version (BSI-CV), Shame Scale for Middle School Students, Sensation Seeking Scale (SSS) and Childhood Trauma Questionnaire (CTQ) were used to assess depression-related behaviors, and event-related potentials (ERPs) were recorded as a measure of cognitive function. The latency of the N1, N2, P3a, P3b, and P50 components of ERPs at the Cz electrode point; P50 amplitude and P50 inhibition (S1/S2) showed significant differences between the 3 groups. CTQ scores also differed across three groups, and the NSSI– and NSSI+ groups showed significant differences in scores on the Shame Scale for Middle School Students. Thus, cognitive function was impaired in adolescents with MDD with NSSI behavior, which was mainly manifested as memory decline, attention and executive function deficits, and low anti-interference ability. We also found that childhood abuse, lack of social support, and a sense of shame contributed to NSSI behavior. These findings provide insight into the risk factors for MDD with NSSI behavior, which can help mental health workers more effectively diagnose and treat these patients.

Evidence for Progressive Cognitive Deficits in Patients With Major Depressive Disorder.

Background: Cognitive deficits have shown progressive feature in major depressive disorder (MDD). However, it remains unknown which component of cognitive function is progressively impaired across episodes of MDD. Here we aim to identify the progressively impaired cognitive components in patients with MDD.Methods: A comprehensive neurocognitive test battery was used to assess the cognitive components (executive function, attention, processing speed, memory, working memory, inhibition, shifting, and verbal fluency) in 35 patients with first-episode MDD (FED), 60 patients with recurrent MDD (RD) and 111 matched healthy controls (HCs). After 6 months of treatment with antidepressant, 20 FED and 36 RD patients achieved clinical remission and completed their second-time neurocognitive tests. Statistical analyses were conducted to identify the impaired cognitive components in the FED and RD groups before and after treatment, and to assess the relationship between the cognitive components and the number of episodes and total illness duration in the MDD patient group.Results: At baseline, both the FED and RD groups showed impairments in all of the cognitive components; the FED and RD groups showed no significant difference in all of the components except for shifting. After remission, only shifting in the RD group showed no significant improvement and remained in an impaired status. Furthermore, shifting was the only component negatively correlated with the number of episodes as well as the total illness duration.Conclusions: Shifting may serve as the progressive cognitive deficit across episodes of MDD.Clinical Trials Registration: Registry name: HPA function and MRI study of trauma-related depression; Registration number: ChiCTR1800014591; URL: http://www.chictr.org.cn/edit.aspx?pid=24669&htm=4.

Interleukin-1 family and serotonin transporter in first-episode, drug-naive major depressive disorder: A pilot study

Abnormalities of neuroinflammatory process and serotonergic system have been reported in major depressive disorder (MDD). However, most previous studies were performed in recurrent MDD and only a few studies explored the interaction of the two systems. This study examined both systems concurrently and their clinical relevance in first-episode drug-naive MDD. Thirty-four MDD patients and 34 age and gender matched healthy controls (HC) were recruited. Plasma concentrations of the cytokines of interleukin-1 (IL-1) family, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type 2 (IL-1R2) were measured using enzyme-linked immune-sorbent assays. The serotonin transporter (SERT) availability in midbrain, thalamus, caudate, and putamen was examined by single-photon emission computed tomography with 123I-ADAM. There were significantly lower concentrations of pro-inflammatory IL-1β and its inhibitor, IL-1R2 in MDD than HC. The SERT availability was at the same level between groups. A negative association between IL-1Ra concentration and the SERT availability in midbrain was observed in MDD but not in HC. Both IL-1β concentration and the SERT availability in caudate negatively correlated with depression severity and the effect of IL-1β was not moderated or mediated by the SERT. In conclusion, this study demonstrated the involvement of IL-1 family in the early stage of MDD, especially for IL-1β. SERT was not the main central target of altered IL-1β and these two systems might contribute to MDD by different mechanisms. The pathophysiology might be varied between early and recurrent MDD and tuning treatment strategies at different clinical stages might be needed.

Altered Static and Dynamic Functional Connectivity of Habenula Associated With Suicidal Ideation in First-Episode, Drug-Naïve Patients With Major Depressive Disorder.

Investigating the neurobiological mechanism of suicidal ideation (SI) in major depressive disorder (MDD) may be beneficial to prevent the suicidal behavior. Mounting evidence showed that habenula contributed to the etiology of MDD. The habenula is a key brain region that links the forebrain to midbrain, crucial for the processing of reward and aversion. The aim of the present study was to identify whether first-episode, drug-naive MDD patients with SI displayed altered habenula neural circuitry. Forty-three and 38 drug-naïve patients with first-episode MDD with or without SI (SI+/– group) and 35 healthy control subjects (HC) underwent resting-state functional magnetic resonance imaging. The whole-brain habenula static (sFC) and dynamic functional connectivity (dFC) were calculated to identify regions showing significant difference among these three groups followed by region of interest to region of interest post hoc analysis. For sFC, compared with SI– and HC groups, SI+ group showed decreased sFC from habenula to the precuneus and the inferior frontal gyrus. Patients with MDD displayed increased sFC from habenula to the putamen but decreased sFC to the precentral gyrus. For dFC, SI+ group showed increased dFC from habenula to the superior temporal gyrus, the precuneus, but decreased dFC to the lingual gyrus, the postcentral gyrus, when comparing with SI– and HC groups. Patients with MDD, regardless of SI, displayed decreased dFC from the habenula to the angular gyrus. These findings provide evidence that SI in first-episode, drug-naïve patients with MDD may be related to an abnormality in habenula neural circuitry, which may provide the theoretical basis of novel treatments.

Brain structural network alterations related to serum cortisol levels in drug-na\xefve, first-episode major depressive disorder patients: a source-based morphometric study

Higher cortisol levels due to a hyperactive hypothalamic–pituitary–adrenal axis have been reported in patients with major depressive disorder (MDD). Increased cortisol levels change both the brain morphology and function in MDD patients. The multivariate source-based morphometry (SBM) technique has been applied to investigate neuroanatomical changes in some neuropsychiatric diseases, but not MDD. We aimed to examine the alterations in gray matter (GM) networks and their relationship with serum cortisol levels in first-episode, drug-naïve MDD patients using SBM. Forty-two patients with MDD and 39 controls were recruited via interviews. Morning serum cortisol levels were measured, and high-resolution T1-weighted imaging followed by SBM analysis was performed in all participants. The patients had significantly higher serum cortisol levels than the controls. We found two GM sources, which were significantly different between patients with MDD and controls (prefrontal network, p < .01; insula-temporal network, p < .01). Serum cortisol levels showed a statistically significant negative correlation with the loading coefficients of the prefrontal network (r = − 0.354, p = 0.02). In conclusion, increased serum cortisol levels were associated with reductions in the prefrontal network in the early stage of MDD, and SBM may be a useful approach for analyzing structural MRI data.

Functional abnormalities in first-episode major depressive disorder with somatic pain

Abstract Objective Depression has a high incidence of somatic pain, and the mechanism of pain in depressed patients remains unclear. Our study explored brain areas with abnormal activity in first-episode major depressive disorder with somatic pain using resting-state functional magnetic resonance imaging (rfMRI) and the relationship between depression and somatic pain. Methods Thirty-two depressed patients (sixteen with somatic pain and sixteen without somatic pain) diagnosed with major depressive disorder by the Structured Clinical Interview for DSM-IV and thirty-three healthy controls were scanned by rfMRI. Regional homogeneity (ReHo) was used to analyze differences between depressed patients with somatic pain and those without somatic pain. Results ReHo values in the left postcentral gyrus (postcentral_l) and the left precentral gyrus (precentral_l) of the depressed patients with somatic pain were significantly higher than those in the patients without somatic pain (tpostcentral_l = 4.93, ppostcentral_l Conclusions Abnormalities in the left postcentral gyrus and precentral gyrus (sensorimotor area) may play important roles in depressed patients with somatic pain.

Transcranial Direct Current Stimulation as an Add-on Treatment to Cognitive-Behavior Therapy in First Episode Drug-Naïve Major Depression Patients: The ESAP Study Protocol.

Background: Major Depressive Disorder (MDD) affects more than 264 million people worldwide. Current treatments include the use of psychotherapy and/or drugs, however ~30% of patients either do not respond to these treatments, or do not tolerate the side effects associated to the use of pharmacological interventions. Thus, it is important to study non-pharmacological interventions targeting mechanisms not directly involved with the regulation of neurotransmitters. Several studies demonstrated that transcranial Direct Current Stimulation (tDCS) can be effective for symptoms relief in MDD. However, tDCS seems to have a better effect when used as an add-on treatment to other interventions.Methods/Design: This is a study protocol for a parallel, randomized, triple-blind, sham-controlled clinical trial in which a total of 90 drug-naïve, first-episode MDD patients (45 per arm) will be randomized to one of two groups to receive a 6-weeks of CBT combined with either active or sham tDCS to the dorsolateral prefrontal cortex (DLPFC). The primary outcome will depressive symptoms improvement as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) at 6-weeks. The secondary aim is to test whether CBT combined with tDCS can engage the proposed mechanistic target of restoring the prefrontal imbalance and connectivity through the bilateral modulation of the DLPFC, as assessed by changes over resting-state and emotional task eliciting EEG.Discussion: This study evaluates the synergetic clinical effects of CBT and tDCS in the first episode, drug-naïve, patients with MDD. First episode MDD patients provide an interesting opportunity, as their brains were not changed by the pharmacological treatments, by the time course, or by the recurrence of MDD episodes (and other comorbidities).Trial Registration: This study is registered with the United States National Library of Medicine Clinical Trials Registry (NCT03548545). Registered June 7, 2018, clinicaltrials.gov/ct2/show/NCT03548545. Protocol Version 1.

Inverse autonomic stress reactivity in depressed patients with and without prior history of depression

BackgroundThere is a considerable association between major depressive disorder (MDD) and cardiovascular disease, most possibly relying on abnormalities in the autonomic nervous system (ANS)-related cardiac reactivity, although the exact underlying pathophysiological pathway is unclear. This study tends to shed some additional light on this background by investigating ANS reactivity in MDD with respect to previous depression history through an objective stress challenge paradigm. MethodsThe study assessed the effects of an overnight hypothalamus-pituitary-adrenal (HPA) axis stimulation with metyrapone (MET) on baseline ANS activity through linear and non-linear heart rate variability (HRV) measures in the morning of two continuous days in a group of 14 physically healthy, antidepressant-free patients with clinical, non-psychotic MDD, to investigate differences in autonomic reactivity with respect to prior MDD history. ResultsThe main findings of this study include statistically significant time × group interactions with respect to several HRV measures, suggesting substantial differences on autonomic reactivity between patients with and without depression history. Hereby, recurrent-episode MDD patients showed lower vagal activity, while first-episode MDD patients increased PNS activity after HPA axis stimulation. ConclusionsThese findings indicate that HPA axis stimulation in MDD patients leads to inverse vagal response according to MDD history. We suggest that chronic stress system overactivation, as found in MDD, might lead to a progressive inversion of the original stress response through HPA axis and ANS divergence over the course of a recurrent illness. HRV could, thus, represent a significant biomarker in MDD with temporal sensitivity.

Repetitive Transcranial Magnetic Stimulation Combined with Antidepressants for the First Episode of Major Depressive Disorder.

Objectives The aims of this study were to systematically review the efficacy, acceptability, and tolerability of repetitive transcranial magnetic stimulation (rTMS) combined with antidepressants in the treatment of the first major depressive disorder (MDD) episode.Materials and Methods The primary efficacious outcome was the pooled mean-endpoint scores of the Hamilton Depression Rating Scale (HAMD). Rates of response, remission rate, overall discontinuation and discontinuation due to adverse events were also evaluated. Search in the Scopus, PubMed, CINAHL, and Cochrane Controlled Trials Register databases for interesting outcomes was carried out in March 2018.Results A total of 108 randomized patients of two randomized controlled trials were included in this study. The pooled mean- endpoint scores of the HAMD in one, two, and four weeks for rTMS plus antidepressants (citalopram or paroxetine) were greater than that of sham plus the antidepressants. The pooled rates of overall discontinuation and discontinuation rates due to adverse events were not different between the two groups.Conclusion According to a piece of limited evidence, the high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) could accelerate the antidepressant effect of SSRIs in young patients with a first-episode major depressive disorder. However, the acceptability and tolerability of HF-rTMS in the treatment of such patients are no better than an antidepressant alone. However, further well-defined and large sample-size studies of HF-rTMS combined with an antidepressant in MDD should be carried out to warrant these results.