Abnormal expression profile of plasma-derived exosomal microRNAs in patients with treatment-resistant depression

AbstractWhether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.

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Abnormal Neural Basis of Emotional Conflict Control in Treatment-Resistant Depression

Clinical EEG and Neuroscience ◽

10.1177/1550059416631658 ◽

2016 ◽

Vol 48 (2) ◽

pp. 103-110 ◽

Cited By ~ 6

Author(s):

Song Xue ◽

Shanshan Wang ◽

Xia Kong ◽

Jiang Qiu

Keyword(s):

Stroop Task ◽

Event Related Potentials ◽

Frontal Region ◽

Healthy Controls ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Neural Basis ◽

Emotional Conflict ◽

Related Potentials ◽

Resistant Depression

Emotional conflict has received increased attention as a research topic. The objective of this study is to confirm that the processing of emotional conflict is impaired in treatment-resistant depression (TRD). We compared the event-related potentials of 17 patients with TRD and 17 healthy controls during the face-word Stroop task, which is an effective way of assessing the effects of emotional conflict directly. Compared with healthy controls, the accuracy scores of the TRD patients were lower in both “congruent stimuli” and “incongruent stimuli” conditions, and their response times were longer. The TRD patients also had larger N2 amplitudes over the frontal region, regardless of stimulus condition, which might reflect that TRD patients pay more attention to emotional information. A larger P3 amplitude over the frontal region for “incongruent stimuli minus congruent stimuli” was also found among patients with TRD, which indicates interference effects in the Stroop task. The results of this study provide novel behavioral and neurophysiological evidence of anomalies in cognitive inhibition among patients with TRD using the word-face task. These findings not only improve our understanding of deficient inhibition in TRD, but also pave the way for a cognitive neuropsychiatric model of depression.

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S127. Heart Rate Variability in Patients With Treatment-Resistant Depression and Healthy Controls After Treatment With Ketamine

Biological Psychiatry ◽

10.1016/j.biopsych.2019.03.878 ◽

2019 ◽

Vol 85 (10) ◽

pp. S345-S346

Author(s):

Grace Cavanaugh ◽

Dede Greenstein ◽

Cristan Farmer ◽

Carlos Zarate ◽

Jennifer Evans

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Healthy Controls ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression

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Ketamine treatment safety in treatment-resistant depression with somatic comorbidities: focus on dissociation and psychotic symptomatology.

10.21203/rs.3.rs-42473/v2 ◽

2021 ◽

Author(s):

Adam Włodarczyk ◽

Wiesław J. Cubała ◽

Maria Węgielnik-Gałuszko ◽

Mariusz S. Wiglusz

Keyword(s):

Clinical Supervision ◽

Small Sample ◽

Psychotic Symptoms ◽

Acute Administration ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Somatic Comorbidity ◽

Somatic Comorbidities ◽

Resistant Depression ◽

Patients With Epilepsy

Abstract Background and objectives: There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety concerns arise regarding adverse drug reactions and specific subpopulations. The aim of this paper is to investigate the safety of intravenous ketamine treatment concerning dissociative and psychotic measures in TRD inpatients with Major Depressive Disorder (MDD) and Bipolar depression (BP) with somatic comorbidities.Methods: The study population of forty-nine inpatients comprises of MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). This dataset represents an intermittent analysis of an observational study performed for interim modelling of observational learning. The study may be underpowered due to the small sample size. The observations apply to the inhomogeneous TRD population in a single-site with no blinding and are limited to the acute administration. Results: The epilepsy was significantly associated with changes in BPRS over time (p=0.008). Psychotic symptomatology with BPRS scores for comorbid somatic conditions excluding epilepsy turned out to be insignificant (p = 0.198) regardless of the diagnosis. However, for a subgroup of patients with epilepsy substantial fluctuation was seen across all administrations in the time course of the study. Conclusions: In ketamine use, careful consideration of comorbidities and concomitant medication is needed. In ketamine administration, close-clinical supervision is necessary at every visit. Psychotic symptoms must be taken into consideration in planning treatment with TRD patients with epilepsy. Somatic comorbidity may impact dissociative symptomatology. Trial Registration: Study registered: 04DEC2019, clinicaltrials.com no. NCT04226963 https://clinicaltrials.gov/ct2/show/NCT04226963

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Rumination-focused cognitive behaviour therapy for non-responsive chronic depression: an uncontrolled group study

Behavioural and Cognitive Psychotherapy ◽

10.1017/s1352465819000584 ◽

2019 ◽

Vol 48 (3) ◽

pp. 376-381

Author(s):

Stine Bjerrum Moeller ◽

Stephen F. Austin ◽

Morten Hvenegaard ◽

Morten Kistrup ◽

Stine Gran ◽

...

Keyword(s):

Depressive Symptoms ◽

Small Sample ◽

Post Treatment ◽

Chronic Depression ◽

Hamilton Depression Scale ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Cognitive Behaviour ◽

Resistant Depression

AbstractBackground:One-third of patients with depression do not respond satisfactorily to treatment, and approximately 20% of all patients treated for depression develop a chronic depression. One approach to more effective treatment of chronic and treatment-resistant depression is to target rumination – an underlying mechanism implicated in the development and maintenance of depression.Aim:The purpose of this uncontrolled group study was to investigate the feasibility of individual rumination-focused cognitive behavioural therapy (RfCBT) for patients with chronic and treatment-resistant depression.Method:A total of 10 patients with chronic and treatment-resistant depression were offered 12–16 individual sessions of RfCBT. The primary outcome was depressive symptoms as measured by Hamilton Depression Scale at pre-, post- and 3-month follow-up. Secondary symptoms measured included self-reported rumination and worry.Results:There was a significant reduction in depressive symptoms (p < 0.05), rumination (p < 0.01) and worry (p < 0.5) from pre- to post-treatment. Half of the participants (n = 5) showed significant reliable change on levels of depressive symptoms post-treatment. The reduction in depressive symptoms, rumination and worry were maintained at follow-up.Conclusions:RfCBT was associated with significant reductions in depressive symptoms in a small sample with chronic and treatment-resistant depression. Despite limitations of being a small uncontrolled study with limited follow-up, these results are promising in a difficult to treat population. RfCBT warrants further systematic evaluation.

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Structural brain characteristics in treatment-resistant depression: review of magnetic resonance imaging studies

BJPsych Open ◽

10.1192/bjo.2019.58 ◽

2019 ◽

Vol 5 (5) ◽

Cited By ~ 3

Author(s):

Margit Philomène C. Klok ◽

Philip. F. van Eijndhoven ◽

Miklos Argyelan ◽

Aart H. Schene ◽

Indira Tendolkar

Keyword(s):

White Matter ◽

Anterior Cingulate ◽

Cochrane Library ◽

Precentral Gyrus ◽

Healthy Controls ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Brain Changes ◽

Resistant Depression ◽

Structural Brain

Background Major depressive disorder (MDD) has been related to structural brain characteristics that are correlated with the severity of disease. However, the correlation of these structural changes is less well clarified in treatment-resistant depression (TRD). Aims To summarise the existing literature on structural brain characteristics in TRD to create an overview of known abnormalities of the brain in patients with MDD, to form hypotheses about the absence or existence of a common pathophysiology of MDD and TRD. Method A systematic search of PubMed and the Cochrane Library for studies published between 1998 and August of 2016 investigating structural brain changes in patients with TRD compared with healthy controls or patients with MDD. Results Fourteen articles are included in this review. Lower grey matter volume (GMV) in the anterior cingulate cortex, right cerebellum, caudate nucleus, superior/medial frontal gyrus and hippocampus does not seem to differentiate TRD from milder forms of MDD. However, lower GMV in the putamen, inferior frontal gyrus, precentral gyrus, angular- and post-central gyri together with specific mainly parietal white matter tract changes seem to be more specific structural characteristics of TRD. Conclusions The currently available data on structural brain changes in patients with TRD compared with milder forms of MDD and healthy controls cannot sufficiently distinguish between a ‘shared continuum hypothesis’ and a ‘different entity hypothesis’. Our review clearly suggests that although there is some overlap in affected brain regions between milder forms of MDD and TRD, TRD also comes with specific alterations in mainly the putamen and parietal white matter tracts. Declaration of interest None.

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Central nervous system-related safety and tolerability of add-on ketamine to antidepressant medication in treatment-resistant depression: focus on the unique safety profile of bipolar depression

Therapeutic Advances in Psychopharmacology ◽

10.1177/20451253211011021 ◽

2021 ◽

Vol 11 ◽

pp. 204512532110110

Author(s):

Adam Włodarczyk ◽

Wiesław J. Cubała ◽

Maria Gałuszko-Węgielnik ◽

Joanna Szarmach

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Rating Scale ◽

Bipolar Depression ◽

Small Sample Size ◽

Small Sample ◽

Mood Stabilizers ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression

Background: There is evidence supporting the use of ketamine in treatment-resistant depression (TRD). However, there are some safety and tolerability concerns associated with ketamine. This study aimed to investigate ketamine’s safety and tolerability to the central nervous system and to assess the relationship between dissociative symptomology and psychometric outcomes during and after intravenous ketamine treatment concurrent with treatment by varying psychotropic medications in treatment-refractory inpatients with major depressive disorder (MDD) and bipolar disorder (BP). Methods: A total of 49 patients with MDD and BP were included in this study. The subjects were administered ketamine and were assessed for changes using an observational protocol. Results: No antidepressants were associated with psychomimetic symptomatology except for citalopram ( p = 0.019). Patients treated with citalopram showed a higher intensity of psychomimetic symptomatology. The use of classic mood-stabilizers was significantly associated with an increase in psychomimetic symptomatology according to the Brief Psychiatric Rating Scale (BPRS; lamotrigine p = 0.009, valproate p = 0.048, lithium p = 0.012). No sequelae were observed. Conclusions: Despite the limitations that this study may be underpowered due to the small sample size, the sample consisted of a heterogeneous TRD population in a single site, and there no blinding of who underwent only acute ketamine administration, our observations indicate ketamine use requires close safety and tolerability monitoring with regards to psychomimetic and dissociative symptoms in TRD-BP and careful management for MDD patients. ClinicalTrials.gov identifier: NCT04226963

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Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts

Molecular Psychiatry ◽

10.1038/s41380-021-01062-9 ◽

2021 ◽

Author(s):

Chiara Fabbri ◽

Saskia P. Hagenaars ◽

Catherine John ◽

Alexander T. Williams ◽

Nick Shrine ◽

...

Keyword(s):

Primary Care ◽

Clinical Characteristics ◽

Antidepressant Drugs ◽

Demographic Characteristics ◽

Polygenic Risk Score ◽

Healthy Controls ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Genetic Characteristics ◽

Resistant Depression

AbstractTreatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71–88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

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Somatic Comorbidities and Cardiovascular Safety in Ketamine Use for Treatment-Resistant Depression

Medicina ◽

10.3390/medicina57030274 ◽

2021 ◽

Vol 57 (3) ◽

pp. 274

Author(s):

Joanna Szarmach ◽

Wiesław Jerzy Cubała ◽

Adam Włodarczyk ◽

Maria Gałuszko-Węgielnik

Keyword(s):

Diabetes Mellitus ◽

Blood Pressure ◽

Heart Rate ◽

Small Sample ◽

Tolerability Profile ◽

Acute Administration ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Somatic Comorbidities ◽

Resistant Depression

Background and Objectives: There is evidence for ketamine efficacy in treatment-resistant depression (TRD). Several safety and tolerability concerns arise that some psychotropic agents may provide blood pressure or/and heart rate alterations. The aim of this study is to review blood pressure measurements in course of the treatment with ketamine on treatment refractory inpatients with somatic comorbidities in the course of MDD and BP. Materials and Methods: The study population of 49 patients comprised MDD and BP subjects treated with ketamine registered in the naturalistic observational protocol of treatment-resistant mood disorders (NCT04226963). Results: The conducted analysis showed that among people suffering from hypertension there is a higher increase in systolic blood pressure (RR) after infusion 2 (p = 0.004) than among people who do not suffer from hypertension. Patients with hypertension have a higher increase in diastolic RR compared to those not suffering from hypertension (p = 0,038). Among the subjects with diabetes mellitus, significant differences occurred for infusions 2 (p = 0.020), 7 (p = 0.020), and 8 (p = 0.035) for heart rate (HR), compared to subjects without diabetes mellitus. A higher increase in diastolic RR was noted in the group of subjects suffering from diabetes mellitus (p = 0.010) compared to those who did not. In the hyperlipidemic patients studied, a significantly greater decrease in HR after infusion 5 (p = 0.031) and systolic RR after infusion 4 (p = 0.036) was noted compared to nonpatients. People after a stroke had significantly higher increases in diastolic RR after infusions 4 (p = 0.021) and 6 (p = 0.001) than those who did not have a stroke. Patients suffering from epilepsy had a significantly greater decrease in systolic RR after the 8th infusion (p = 0.017) compared to those without epilepsy. Limitations: The study may be underpowered due to the small sample size. The observations apply to inhomogeneous TRD population in a single-site with no blinding and are limited to the acute administration. Conclusions: This study supports evidence for good safety and tolerability profile for short-term IV ketamine use in TRD treatment. However, risk mitigation measures are to be considered in patients with metabolic and cardiovascular comorbidities.

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Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

International Journal of Molecular Sciences ◽

10.3390/ijms21072444 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2444 ◽

Cited By ~ 1

Author(s):

Naoki Kiyosawa ◽

Kenji Watanabe ◽

Yoshiyuki Morishima ◽

Takeshi Yamashita ◽

Naoharu Yagi ◽

...

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Target Genes ◽

Enrichment Analysis ◽

Quantitative Information ◽

Pathway Enrichment Analysis ◽

Risk Patients ◽

Novel Biomarkers ◽

Positive Correlations ◽

Potential Biomarkers

Novel biomarkers are desired to improve risk management for patients with atrial fibrillation (AF). We measured 179 plasma miRNAs in 83 AF patients using multiplex qRT-PCR. Plasma levels of eight (i.e., hsa-miR-22-3p, hsa-miR-128-3p, hsa-miR-130a-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-148b-3p, hsa-miR-497-5p, hsa-miR-652-3p) and three (i.e., hsa-miR-144-5p, hsa-miR-192-5p, hsa-miR-194-5p) miRNAs showed positive and negative correlations with CHA2DS2-VASc scores, respectively, which also showed negative and positive correlations with catheter ablation (CA) procedure, respectively, within the follow-up observation period up to 6-month after enrollment. These 11 miRNAs were functionally associated with TGF-β signaling and androgen signaling based on pathway enrichment analysis. Seven of possible target genes of these miRNAs, namely TGFBR1, PDGFRA, ZEB1, IGFR1, BCL2, MAPK1 and DICER1 were found to be modulated by more than four miRNAs of the eleven. Of them, TGFBR1, PDGFRA, ZEB1 and BCL2 are reported to exert pro-fibrotic functions, suggesting that dysregulations of these eleven miRNAs may reflect pro-fibrotic condition in the high-risk patients. Although highly speculative, these miRNAs may potentially serve as potential biomarkers, providing mechanistic and quantitative information for pathophysiology in daily clinical practice with AF such as possible pro-fibrotic state in left atrium, which would enhance the risk of stroke and reduce the preference for performing CA.

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