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Nature Medicine Feb 2024Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for... (Randomized Controlled Trial)
Randomized Controlled Trial
Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).
Topics: Humans; Double-Blind Method; Magnetic Resonance Imaging; Prefrontal Cortex; Transcranial Magnetic Stimulation; Treatment Outcome; Depressive Disorder, Treatment-Resistant
PubMed: 38228914
DOI: 10.1038/s41591-023-02764-z -
Journal of Affective Disorders Apr 2024Investigation on specific biomarkers for diagnostic or prognostic usage in mental diseases and especially bipolar disorder BD seems to be one outstanding field in...
INTRODUCTION
Investigation on specific biomarkers for diagnostic or prognostic usage in mental diseases and especially bipolar disorder BD seems to be one outstanding field in current research. Serum neurofilament light (sNfL), a marker for neuro-axonal injury, is increased in various acute and chronic neurological disorders, but also neuro-psychiatric conditions, including affective disorders. The aim of our study was to determine a potential relation between a neuron-specific marker like sNfL and different clinical states of BD.
METHODS
In the current investigation, 51 patients with BD and 35 HC were included. Mood ratings with the Hamilton depression scale (HAMD) and the Young mania rating scale (YMRS) have been included. Illness duration was defined as the period from the time of diagnosis out of self-report and medical records. sNFL was quantified by a commercial ultrasensitive single molecule array (Simoa).
RESULTS
There was a significant positive correlation between the number of manic episodes in the past and sNfL, controlled for age and duration of illness. (R = 0.49, p = 0.03) Depressive episodes were not associated to sNfL values. (R = 0.311, p = n.s.) Patients with >3 years of illness duration showed significantly higher levels of sNfL (M18.59; SD 11.89) than patients with shorter illness duration (M = 12.38, p = 0.03) and HC (M = 11.35, p = 0.02). Patients with <3 years of illness and HC did not differ significantly in sNfL levels.
DISCUSSION
Interestingly, individuals with BD and HC did not differ in sNFL levels in general. Nevertheless, looking at the BD cohort more specifically, we found that individuals with BD with longer duration of illness (>3 years) had higher levels of sNfL than those with an illness duration below 3 years. Our results confirm previous reports on the relation of neuro-axonal injury as evidenced by sNfL and illness specific variables in bipolar disorder. Further studies are needed to clarify if sNfL may predict the disease course and/or indicated response to treatment regimes.
Topics: Humans; Bipolar Disorder; Intermediate Filaments; Mood Disorders; Psychotic Disorders; Prognosis; Biomarkers
PubMed: 38215991
DOI: 10.1016/j.jad.2024.01.088 -
Translational Psychiatry Jan 2024Nearly a quarter of bipolar disorder (BD) patients were misdiagnosed as major depressive disorder (MDD) patients, which cannot be corrected until mania/hypomania...
Nearly a quarter of bipolar disorder (BD) patients were misdiagnosed as major depressive disorder (MDD) patients, which cannot be corrected until mania/hypomania develops. It is important to recognize these obstacles so that the appropriate treatment can be initiated. Thus, we sought to distinguish patients with BD from MDD, especially to identify misdiagnosed BD before mania/hypomania, and further explore potential trait features that allow accurate differential diagnosis independent of state matters. Functional magnetic resonance imaging scans were performed at baseline on 92 MDD patients and 48 BD patients. The MDD patients were then followed up for more than two years. After follow-up, 23 patients transformed into BD (tBD), and 69 patients whose diagnoses remained unchanged were eligible for unipolar depression (UD). A support vector machine classifier was trained on the amygdala-based functional connectivity (FC) of 48 BD and 50 UD patients using a novel region-based feature selection. Then, the classifier was tested on the dataset, encompassing tBD and the remaining UD. It performed well for known BD and UD and can also distinguish tBD from UD with an accuracy of 81%, sensitivity of 82.6%, specificity of 79%, and AUC of 74.6%, respectively. Feature selection results revealed that ten regions within the cortico-limbic neural circuit contributed most to classification. Furthermore, in the FC comparisons among diseases, BD and tBD shared almost overlapped FC patterns in the cortico-limbic neural circuit, and both of them presented pronounced differences in most regions within the circuit compared with UD. The FC values of the most discriminating brain regions had no prominent correlations with the severity of depression, anxiety, and mania/hypomania (FDR correction). It suggests that BD possesses some trait features in the cortico-limbic neural circuit, rendering it dichotomized by the classifier based on known-diagnosis data.
Topics: Humans; Bipolar Disorder; Mania; Depressive Disorder, Major; Magnetic Resonance Imaging; Follow-Up Studies; Support Vector Machine; Mood Disorders
PubMed: 38191549
DOI: 10.1038/s41398-023-02703-z -
MedRxiv : the Preprint Server For... Dec 2023Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments.
IMPORTANCE
Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments.
OBJECTIVE
To perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment.
DESIGN
Double blind randomized controlled trial.
SETTING
Multicenter.
PARTICIPANTS
Patients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study.
INTERVENTIONS
Either sertraline or placebo during 8 weeks (stage 1), and according to response a second line of treatment for 8 additional weeks (stage 2).
MAIN OUTCOMES AND MEASURES
To identify a data-driven pattern of symptom variations during these two stages, we performed a Principal Component Analysis (PCA) on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas and manic-like symptoms, resulting in a univariate measure of clinical improvement. We then investigated how initial clinical and neural factors predicted this measure during stage 1. To do so, we extracted resting-state global brain connectivity (GBC) at baseline at the individual level using a whole-brain functional network parcellation. In turn, we computed a linear model for each brain parcel with individual data-driven clinical improvement scores during stage 1 for each group.
RESULTS
192 patients (127 women), age 37.7 years old (standard deviation: 13.5), were included. The first PC (PC1) capturing 20% of clinical variation was similar across treatment groups at stage 1 and stage 2, suggesting a reproducible pattern of symptom improvement. PC1 patients' scores significantly differed according to treatment during stage 1, whereas no difference of response was evidenced between groups with the Clinical Global Impressions (CGI). Baseline GBC correlated to stage 1 PC1 scores in the sertraline, but not in the placebo group.
CONCLUSIONS AND RELEVANCE
Using data-driven reduction of symptoms scales, we identified a common profile of symptom improvement across placebo and sertraline. However, the neural patterns of baseline that mapped onto symptom improvement distinguished between treatment and placebo. Our results underscore that mapping from data-driven symptom improvement onto neural circuits is vital to detect treatment-responsive neural profiles that may aid in optimal patient selection for future trials.
PubMed: 38168378
DOI: 10.1101/2023.12.15.23300019 -
Journal of Affective Disorders Mar 2024It is estimated that up to 50 % of people with bipolar disorder (BD) also have comorbid post-traumatic stress disorder (PTSD). However, little is known about the...
BACKGROUND
It is estimated that up to 50 % of people with bipolar disorder (BD) also have comorbid post-traumatic stress disorder (PTSD). However, little is known about the presentation and treatment of people with this comorbidity.
METHODS
Data from 577 individuals diagnosed with bipolar disorder participating in the Heinz C. Prechter Longitudinal Study of BD were explored at baseline, year two and four. Three trauma groups were created: (i) one trauma (n = 75), (ii) multiple traumas (n = 417), and comorbid PTSD (n = 85). Measures of depression, mania, sleep, number of hospitalisations, suicide attempts, and medication use were analysed using regression modelling to determine differences between the three trauma groups.
RESULTS
There was an increase in depression, mania, and sleep scores and a higher number of hospitalisations in participants with comorbid PTSD compared to those experiencing one trauma. Additionally, increased mania and depression scores were reported in participants experiencing multiple traumas compared to those with one trauma. There was no difference in medication use between those who experienced one trauma compared to those with comorbid PTSD.
LIMITATIONS
The trauma groups may include confounding with more participants experiencing PTSD than reported in this study due to screening processes. Additionally, the severity of trauma was not recorded, therefore number of traumas was utilised as a proxy.
CONCLUSION
Comorbid BD and PTSD is associated with worse symptom scores compared to participants reporting one trauma. Clinical implications include the addition of trauma-informed care to clinical settings to identify PTSD to provide appropriate treatments.
Topics: Humans; Stress Disorders, Post-Traumatic; Bipolar Disorder; Longitudinal Studies; Mania; Comorbidity; Multiple Trauma
PubMed: 38163569
DOI: 10.1016/j.jad.2023.12.058 -
Journal of Affective Disorders Mar 2024Inflammation and immunological alterations, such as T-cell and cytokine changes, are implicated in bipolar disorder (BD), with some evidence linking them to brain...
BACKGROUND
Inflammation and immunological alterations, such as T-cell and cytokine changes, are implicated in bipolar disorder (BD), with some evidence linking them to brain structural changes (e.g., cortical thickness (CT), gray matter (GM) volume and white matter (WM) microstructure). However, the connection between specific peripheral cell types, such as T-cells, and neuroimaging in BD remains scarcely investigated.
AIMS OF THE STUDY
This study aims to explore the link between T-cell immunophenotype and neuroradiological findings in BD.
METHODS
Our study investigated 43 type I BD subjects (22 depressive, 21 manic) and 26 healthy controls (HC), analyzing T lymphocyte immunophenotype and employing neuroimaging to assess CT for GM and fractional anisotropy (FA) for WM.
RESULTS
In lymphocyte populations, BD patients exhibited elevated CD4+ and CD4+ central memory (T) cells frequencies, but lower CD8+ effector memory (T) and terminal effector memory (T) cells. Neuroimaging analysis revealed reduced CT in multiple brain regions in BD patients; and significant negative correlations between CD4 + T levels and CT of precuneus and fusiform gyrus. Tract-based spatial statistics (TBSS) analysis showed widespread alteration in WM microstructure in BD patients, with negative and positive correlations respectively between FA and radial diffusivity (RD) and CD4 + T. Additionally, positive and negative correlations were found respectively between FA and RD and the CD8 + T and CD8 + T subsets.
CONCLUSIONS
Our research revealed distinct T lymphocyte changes and brain structure alterations in BD, underscoring possible immune-brain interactions, warranting further study and therapeutic exploration.
Topics: Humans; Bipolar Disorder; White Matter; Diffusion Tensor Imaging; T-Lymphocytes; Brain; Anisotropy
PubMed: 38154587
DOI: 10.1016/j.jad.2023.12.054 -
Scientific Reports Dec 2023Patients with bipolar disorder (BD) show higher immuno-inflammatory setpoints, with in vivo alterations in white matter (WM) microstructure and post-mortem infiltration...
Patients with bipolar disorder (BD) show higher immuno-inflammatory setpoints, with in vivo alterations in white matter (WM) microstructure and post-mortem infiltration of T cells in the brain. Cytotoxic CD8 T cells can enter and damage the brain in inflammatory disorders, but little is known in BD. Our study aimed to investigate the relationship between cytotoxic T cells and WM alterations in BD. In a sample of 83 inpatients with BD in an active phase of illness (68 depressive, 15 manic), we performed flow cytometry immunophenotyping to investigate frequencies, activation status, and expression of cytotoxic markers in CD8 and tested for their association with diffusion tensor imaging (DTI) measures of WM microstructure. Frequencies of naïve and activated CD8 cell populations expressing Perforin, or both Perforin and Granzyme, negatively associated with WM microstructure. CD8 Naïve cells negative for Granzyme and Perforin positively associates with indexes of WM integrity, while the frequency of CD8 memory cells negatively associates with index of WM microstructure, irrespective of toxins expression. The resulting associations involve measures representative of orientational coherence and myelination of the fibers (FA and RD), suggesting disrupted oligodendrocyte-mediated myelination. These findings seems to support the hypothesis that immunosenescence (less naïve, more memory T cells) can detrimentally influence WM microstructure in BD and that peripheral CD8 T cells may participate in inducing an immune-related WM damage in BD mediated by killer proteins.
Topics: Humans; Bipolar Disorder; White Matter; Diffusion Tensor Imaging; CD8-Positive T-Lymphocytes; Granzymes; Perforin; Anisotropy
PubMed: 38097657
DOI: 10.1038/s41598-023-49146-6 -
EClinicalMedicine Dec 2023There is an urgent need to better understand and prevent relapse in major depressive disorder (MDD). We explored the differential impact of various MDD relapse...
Differential impact of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment on affect fluctuations and individual affect networks and impact on relapse: a secondary analysis of a randomised controlled trial.
BACKGROUND
There is an urgent need to better understand and prevent relapse in major depressive disorder (MDD). We explored the differential impact of various MDD relapse prevention strategies (pharmacological and/or psychological) on affect fluctuations and individual affect networks in a randomised setting, and their predictive value for relapse.
METHODS
We did a secondary analysis using experience sampling methodology (ESM) data from individuals with remitted recurrent depression that was collected alongside a randomised controlled trial that ran in the Netherlands, comparing: (I) tapering antidepressants while receiving preventive cognitive therapy (PCT), (II) combining antidepressants with PCT, or (III) continuing antidepressants without PCT, for the prevention of depressive relapse, as well as ESM data from 11 healthy controls. Participants had multiple past depressive episodes, but were remitted for at least 8 weeks and on antidepressants for at least six months. Exclusion criteria were: current (hypo)mania, current alcohol or drug abuse, anxiety disorder that required treatment, psychological treatment more than twice per month, a diagnosis of organic brain damage, or a history of bipolar disorder or psychosis. Fluctuations (within-person variance, root mean square of successive differences, autocorrelation) in negative and positive affect were calculated. Changes in individual affect networks during treatment were modelled using time-varying vector autoregression, both with and without applying regularisation. We explored whether affect fluctuations or changes in affect networks over time differed between treatment conditions or relapse outcomes, and predicted relapse during 2-year follow-up. This ESM study was registered at ISRCTN registry, ISRCTN15472145.
FINDINGS
Between Jan 1, 2014, and Jan 31, 2015, 72 study participants were recruited, 42 of whom were included in the analyses. We found no indication that affect fluctuations differed between treatment groups, nor that they predicted relapse. We observed large individual differences in affect network structure across participants (irrespective of treatment or relapse status) and in healthy controls. We found no indication of group-level differences in how much networks changed over time, nor that changes in networks over time predicted time to relapse (regularised models: hazard ratios [HR] 1063, 95% CI <0.0001->10 000, p = 0.65; non-regularised models: HR 2.54, 95% CI 0.23-28.7, p = 0.45) or occurrence of relapse (regularised models: odds ratios [OR] 22.84, 95% CI <0.0001->10 000, p = 0.90; non-regularised models: OR 7.57, 95% CI 0.07-3709.54, p = 0.44) during complete follow-up.
INTERPRETATION
Our findings should be interpreted with caution, given the exploratory nature of this study and wide confidence intervals. While group-level differences in affect dynamics cannot be ruled out due to low statistical power, visual inspection of individual affect networks also revealed no meaningful patterns in relation to MDD relapse. More studies are needed to assess whether affect dynamics as informed by ESM may predict relapse or guide personalisation of MDD relapse prevention in daily practice.
FUNDING
The Netherlands Organisation for Health Research and Development, Dutch Research Council, University of Amsterdam.
PubMed: 38078193
DOI: 10.1016/j.eclinm.2023.102329 -
Research Square Dec 2023Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide...
BACKGROUND
Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.
RESULTS
We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.
CONCLUSIONS
Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
PubMed: 38077040
DOI: 10.21203/rs.3.rs-3677630/v1