Associations between C-reactive protein and individual symptoms of depression in a lower-middle income country.

BACKGROUND: Data on associations between inflammation and depressive symptoms largely originate from high income population settings, despite the greatest disease burden in major depressive disorder being attributed to populations in lower-middle income countries (LMICs). AIMS: We assessed the prevalence of low-grade inflammation in adults with treatment-resistant depression (TRD) in Pakistan, an LMIC, and investigated associations between peripheral C-reactive protein (CRP) levels and depressive symptoms. METHOD: This is a secondary analysis of two randomised controlled trials investigating adjunctive immunomodulatory agents (minocycline and simvastatin) for Pakistani adults with TRD (n = 191). Logistic regression models were built to assess the relationship between pre-treatment CRP (≥ or <3 mg/L) and individual depressive symptoms measured using the Hamilton Depression Rating Scale. Descriptive statistics and regression were used to assess treatment response for inflammation-associated symptoms. RESULTS: High plasma CRP (≥3 mg/L) was detected in 87% (n = 146) of participants. Early night insomnia (odds ratio 2.33, 95% CI 1.16-5.25), early morning waking (odds ratio 2.65, 95% CI 1.29-6.38) and psychic anxiety (odds ratio 3.79, 95% CI 1.39-21.7) were positively associated, while gastrointestinal (odds ratio 0.38, 95% CI 0.14-0.86) and general somatic symptoms (odds ratio 0.34, 95% CI 0.14-0.74) were negatively associated with inflammation. Minocycline, but not simvastatin, improved symptoms positively associated with inflammation. CONCLUSIONS: The prevalence of inflammation in this LMIC sample with TRD was higher than that reported in high income countries. Insomnia and anxiety symptoms may represent possible targets for personalised treatment with immunomodulatory agents in people with elevated CRP. These findings require replication in independent clinical samples.

Use of virtual reality in bipolar disorder: a systematic review.

Virtual reality (VR) is a technology that allows to interact with recreated digital environments and situations with enhanced realism. VR has shown good acceptability and promise in different mental health conditions. No systematic review has evaluated the use of VR in Bipolar Disorder (BD). This PRISMA-compliant systematic review searched PubMed and Web of Science databases (PROSPERO: CRD42023467737) to identify studies conducted in individuals with BD in which VR was used. Results were systematically synthesized around four categories (cognitive and functional evaluation, clinical assessment, response to VR and safety/acceptability). Eleven studies were included (267 individuals, mean age = 36.6 years, 60.7% females). Six studies using VR to carry out a cognitive evaluation detected impairments in neuropsychological performance and delayed reaction times. VR was used to assess emotional regulation. No differences in well-being between VR-based and physical calm rooms were found. A VR-based stress management program reduced subjective stress, depression, and anxiety levels. VR-based cognitive remediation improved cognition, depressive symptoms, and emotional awareness. 48.7% of the individuals with BD considered VR-based cognitive remediation 'excellent', whereas 28.2% considered it 'great'. 87.2% of individuals did not report any side effects. 81.8% of studies received a global quality rating of moderate. Emerging data point towards a promising use of VR in BD as an acceptable assessment/intervention tool. However, multiple unstudied domains as comorbidity, relapse and prodromal symptoms should be investigated. Research on children and adolescents is also recommended. Further research and replication of findings are required to disentangle which VR-interventions for which populations and outcomes are effective.

Enhanced network synchronization connectivity following transcranial direct current stimulation (tDCS) in bipolar depression: Effects on EEG oscillations and deep learning-based predictors of clinical remission.

AIM: To investigate oscillatory networks in bipolar depression, effects of a home-based tDCS treatment protocol, and potential predictors of clinical response. METHODS: 20 participants (14 women) with bipolar disorder, mean age 50.75 ±â€¯10.46 years, in a depressive episode of severe severity (mean Montgomery-Åsberg Rating Scale (MADRS) score 24.60 ±â€¯2.87) received home-based transcranial direct current stimulation (tDCS) treatment for 6 weeks. Clinical remission defined as MADRS score < 10. Resting-state EEG data were acquired at baseline, prior to the start of treatment, and at the end of treatment, using a portable 4-channel EEG device (electrode positions: AF7, AF8, TP9, TP10). EEG band power was extracted for each electrode and phase locking value (PLV) was computed as a functional connectivity measure of phase synchronization. Deep learning was applied to pre-treatment PLV features to examine potential predictors of clinical remission. RESULTS: Following treatment, 11 participants (9 women) attained clinical remission. A significant positive correlation was observed with improvements in depressive symptoms and delta band PLV in frontal and temporoparietal regional channel pairs. An interaction effect in network synchronization was observed in beta band PLV in temporoparietal regions, in which participants who attained clinical remission showed increased synchronization following tDCS treatment, which was decreased in participants who did not achieve clinical remission. Main effects of clinical remission status were observed in several PLV bands: clinical remission following tDCS treatment was associated with increased PLV in frontal and temporal regions and in several frequency bands, including delta, theta, alpha and beta, as compared to participants who did not achieve clinical remission. The highest deep learning prediction accuracy 69.45 % (sensitivity 71.68 %, specificity 66.72 %) was obtained from PLV features combined from theta, beta, and gamma bands. CONCLUSIONS: tDCS treatment enhances network synchronization, potentially increasing inhibitory control, which underscores improvement in depressive symptoms. Baseline EEG-based measures might aid predicting clinical response.

Identifying digital biomarkers of illness activity and treatment response in bipolar disorder with a novel wearable device (TIMEBASE): protocol for a pragmatic observational clinical study.

BACKGROUND: Bipolar disorder is highly prevalent and consists of biphasic recurrent mood episodes of mania and depression, which translate into altered mood, sleep and activity alongside their physiological expressions. AIMS: The IdenTifying dIgital bioMarkers of illnEss activity and treatment response in BipolAr diSordEr with a novel wearable device (TIMEBASE) project aims to identify digital biomarkers of illness activity and treatment response in bipolar disorder. METHOD: We designed a longitudinal observational study including 84 individuals. Group A comprises people with acute episode of mania (n = 12), depression (n = 12 with bipolar disorder and n = 12 with major depressive disorder (MDD)) and bipolar disorder with mixed features (n = 12). Physiological data will be recorded during 48 h with a research-grade wearable (Empatica E4) across four consecutive time points (acute, response, remission and episode recovery). Group B comprises 12 people with euthymic bipolar disorder and 12 with MDD, and group C comprises 12 healthy controls who will be recorded cross-sectionally. Psychopathological symptoms, disease severity, functioning and physical activity will be assessed with standardised psychometric scales. Physiological data will include acceleration, temperature, blood volume pulse, heart rate and electrodermal activity. Machine learning models will be developed to link physiological data to illness activity and treatment response. Generalisation performance will be tested in data from unseen patients. RESULTS: Recruitment is ongoing. CONCLUSIONS: This project should contribute to understanding the pathophysiology of affective disorders. The potential digital biomarkers of illness activity and treatment response in bipolar disorder could be implemented in a real-world clinical setting for clinical monitoring and identification of prodromal symptoms. This would allow early intervention and prevention of affective relapses, as well as personalisation of treatment.

Cognitive correlates of psychopathology in functional/dissociative seizures and non-lesional epilepsy: An exploratory study.

OBJECTIVE: To explore the relationship between cognitive functioning and psychopathological features in Functional/Dissociative Seizures (FDS), and test whether this differs from that observed in epilepsy. METHODS: We recruited a cross-sectional sample of adults (age > 18) with a diagnosis of non-lesional epilepsy or FDS between January 2021 and July 2022 (n = 73). Participants completed a series of psychiatric questionnaires and neuropsychological measures. Spearman's Correlation Coefficient was computed between each of the psychiatric and cognitive measures in each group. Fisher's Z test of significance for independent correlation coefficients then tested the significance of the difference between correlation coefficients for the two groups. RESULTS: There were no group differences in neuropsychological test scores. However, people with FDS reported higher seizure severity, depression levels, number of medically unexplained somatic symptoms, and exposure to traumatic events compared to epilepsy. Results of the Fisher's Z-test revealed significant differences in correlation coefficients between groups in two instances. First, in the association between the number of traumatic experiences and cognitive switching (z = 2.77, p = 0.006); the number of traumatic experiences were positively associated with cognitive switching in epilepsy but showed a non-significant negative trend in FDS. Secondly, in the association between vocabulary abilities and the number of medically unexplained symptoms (z = -2.71; p = 0.007); higher vocabulary ability was associated with fewer somatic symptoms in epilepsy, while no such correlation was observed in FDS. SIGNIFICANCE: This study provides preliminary evidence for the complex interplay between cognitive functioning and psychopathology in FDS and epilepsy. Neurocognitive functioning such as vocabulary abilities or attentional switching may play a role in the expression or maintenance of pathological features of FDS.

Home-based transcranial direct current stimulation in bipolar depression: an open-label treatment study of clinical outcomes, acceptability and adverse events.

BACKGROUND: Current treatments for bipolar depression have limited effectiveness, tolerability and acceptability. Transcranial direct current stimulation (tDCS) is a novel non-invasive brain stimulation method that has demonstrated treatment efficacy for major depressive episodes. tDCS is portable, safe, and individuals like having sessions at home. We developed a home-based protocol with real-time remote supervision. In the present study, we have examined the clinical outcomes, acceptability and feasibility of home-based tDCS treatment in bipolar depression. RESULTS: Participants were 44 individuals with bipolar disorder (31 women), mean age 47.27 ± 12.89 years, in current depressive episode of at least moderate severity (mean Montgomery Asberg Depression Rating Scale (MADRS) score 24.59 ± 2.64). tDCS was provided in bilateral frontal montage, F3 anode, F4 cathode, 2 mA, for 30 min, in a 6-week trial, for total 21 sessions, a follow up visit was conducted 5 months from baseline. Participants maintained their current treatment (psychotherapy, antidepressant or mood stabilising medication) or maintained being medication-free. A research team member was present by video conference at each session. 93.2% participants (n = 41) completed the 6-week treatment and 72.7% of participants (n = 32) completed the 5 month follow up. There was a significant improvement in depressive symptoms following treatment (mean MADRS 8.77 ± 5.37) which was maintained at the 5 month follow up (mean MADRS 10.86 ± 6.90), rate of clinical response was 77.3% (MADRS improvement of 50% or greater from baseline), and rate of clinical remission was 47.7% (MADRS rating of 9 or less). Acceptability was endorsed as "very acceptable" or "quite acceptable" by all participants. No participants developed mania or hypomania. CONCLUSIONS: In summary, home-based tDCS with real-time supervision was associated with significant clinical improvements and high acceptability in bipolar depression. Due to the open-label design, efficacy findings are preliminary. TRIAL REGISTRATION: ClinicalTrials.gov number NCT05436613 registered on 23 June 2022 https//www. CLINICALTRIALS: gov/study/NCT05436613.

The Tightrope Study: A cadaveric, biomechanical comparison of generations of suspensory fixation with internal brace for Rockwood grade V AC joint injuries.

BACKGROUND: Surgical treatment of Rockwood grade V AC joint injuries remains varied. We hypothesized that the addition of a second suspensory device between the clavicle and coracoid would yield superior biomechanical results over a single device. We also hypothesized that the addition of an internal brace across the AC joint to a suspensory device would yield superior results over the suspensory device in isolation. METHODS: A total of 24 cadaveric shoulders were dissected and randomized to four groups with four different constructs implanted: Group A: Single AC TightRope (Arthrex Inc., Naples, FL, USA) Group B: Double AC TightRope Group C: Single Knotless AC TightRope (Arthrex Inc., Naples, FL, USA) Group D: Single Knotless AC TightRope with AC InternalBrace Ligament Augmentation (Arthrex Inc., Naples, FL, USA) These were then loaded in the Robotic arm (SIMVITRO) where 250 cycles of 50N of force in the superior plane was applied. Dynamic creep, displacement, translation and stiffness were assessed. RESULTS: Testing was successfully completed for all specimens. There were no failures due to fracture or translation of the clavicle greater than 5mm from the starting position. Reduction was maintained with a mean superior displacement of 1.7 mm (± 1.4 mm). The mean peak to peak displacement, superior and posterior translation, dynamic creep and stiffness did not differ significantly between construct groups. CONCLUSION: This study did not demonstrate any significant biomechanical differences between groups in terms of displacement, translation, creep or stiffness.

Activation of the interleukin-23/Th17 axis in major depression: a systematic review and meta-analysis.

The interleukin-23/Th17 axis is a promising modifiable target for depression. However, its association with depression has not been systematically evaluated. We systematically searched four databases (EMBASE, Web of Science, Pubmed and PsycINFO) for studies comparing patients with major depression and healthy controls for plasma/serum levels of Th17 cells and their canonical cytokines (interleukin-17A [IL-17A], IL-22, granulocyte macrophage colony stimulating factor [GM-CSF]). We also compared counts of Th1, Th2 and Th9 cells between depressed/non-depressed patients and their respective canonical cytokines. We performed random-effects meta-analysis of the standardised mean difference (SMD) in immune measures between groups. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 3154 studies screened, 36 studies were included in meta-analysis. Patients with depression had elevated IL-17A compared to controls (SMD = 0.80 [95% CI 0.03 to 1.58], p = 0.042), an association moderated by antidepressant use (Z = 2.12, p = 0.034). Patients with depression had elevated GM-CSF (SMD = 0.54 [95% CI 0.16 to 0.91], p = 0.0047), and a trend towards higher Th17 counts (SMD = 0.44 [- 0.01 to 0.88], p = 0.052). Whilst the Th2-associated cytokine IL-5 was elevated in depression (SMD = 0.36 [95% CI 0.05 to 0.66], p = 0.02), Th2 cell counts (p = 0.97), Th1 cell counts (p = 0.17) and interferon-γ (p = 0.22) were not. Data for Th9 cells, IL-9 and IL-22 were insufficient for meta-analysis. Respectively, 22, 25 and 5 studies were good, fair and poor in quality. Patients with major depression show peripheral over-activation of the IL-23/Th17 axis. Future interventional studies should test whether this is a modifiable target for depression.

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo.

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (ß = -18.3, 95% CI (-34.3 to -2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.