Treatment resistant depression in the UK: sub-analysis of a European real-world evidence study

AimsTreatment resistant depression (TRD) affects ≤20% of patients with major depressive disorder and is defined as failure to respond to ≥2 different antidepressants in the same major depressive episode (MDE). TRD patients’ outcomes are poor and real-world data from the UK are limited. The Treatment Resistant Depression in Europe Cohort was established to study patients being treated in local, routine clinical practice. The analysis presented here aimed to compare UK-specific data with data from other European countries included in the study.MethodA prospective, multicentre, observational cohort study of TRD patients in Italy, Germany, Spain, Portugal, the Netherlands, the UK and Belgium was conducted. Patients aged 18–74 years with current TRD, Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥20, and initiating a new treatment for depression, were eligible. Data from medical records, clinician assessments and patient-reported questionnaires were collected over time, with follow-up of ≥6 months.ResultData from 411 patients were analysed. At baseline, UK patients (n = 49) had similar depression severity to the whole European cohort (34.7% vs 32.6% of patients categorised as severe based on MADRS score, respectively). Patients had experienced the current MDE for a mean (standard deviation [SD]) of 6.1 (7.9) years vs 2.6 (3.9) years and 14.3% vs 4.9% had experienced ≥5 treatment failures during this time in the UK and whole cohort, respectively. Total mean (SD) Sheehan Disability Scale (SDS) scores of 24.5 (5.1) and 22.4 (5.5) were reported for the UK and whole cohort, respectively. Unemployment and long-term sick leave rates were 38.8% and 20.4% in the UK and 30.2% and 19.0% in the whole cohort, respectively. At 6 months, 8.9% of UK patients were in remission, and 82.2% had not responded to treatment, representing the lowest remission and highest non-response rates across all countries.ConclusionUK patients had been ill for longer and had more prior treatment failures than other countries in the study. They had high work and functional impairment, and the worst treatment outcomes of all the countries studied. UK TRD patients experience high disease burden; there is an unmet need for treatment strategies with better response rates.AcknowledgementsWe thank all participating patients. Study, and medical writing (Costello Medical, UK), funded by Janssen. AHY's independent research is funded by the National Institute for Health Research. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Intranasal Ketamine for Depression in Adults: A Systematic Review and Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials

BackgroundThere is growing interest in glutamatergic agents as a treatment for depression, especially intranasal ketamine, which has become a hot topic in recent years. We aim to assess the efficacy and safety of intranasal ketamine in the treatment of major depressive disorder (MDD), especially treatment-resistant depression (TRD).MethodsWe searched Medline, EMBASE, and the Cochrane Library until April 1, 2020 to identify double-blind, randomized controlled trials with allocation concealment evaluating intranasal ketamine in major depressive episodes. Clinical remission, response, and depressive symptoms were extracted by two independent raters. The outcome measures were Montgomery–Asberg Depression Rating Scale (MADRS) score improved from baseline, clinical response and remission, dissociative symptoms, and common adverse events. The analyses employed a random-effects model.ResultsData were synthesized from five randomized controlled trials (RCTs) employing an intranasal esketamine and one RCT employing intranasal ketamine, representing 840 subjects in parallel arms, and 18 subjects in cross-over designs (n = 858 with MDD, n = 792 with TRD). The weighted mean difference of MADRS score was observed to decrease by 6.16 (95% CI 4.44–7.88) in 2–4 h, 9.96 (95% CI 8.97–10.95) in 24 h, and 4.09 (95% CI 2.18–6.00) in 28 day. The pooled relative risk (RR) was 3.55 (95% CI 1.5–8.38, z = 2.89, and p < 0.001) for clinical remission and 3.22 (95% CI 1.85–5.61, z = 4.14, and p < 0.001) for clinical response at 24 h, while the pooled RR was 1.7 (95% CI 1.28–2.24, z = 3.72, and p < 0.001) for clinical remission and 1.48 (95% CI 1.17–1.86, z = 3.28, and p < 0.001) for clinical response at 28 day. Intranasal ketamine was associated with the occurrence of transient dissociative symptoms and common adverse events, but no persistent psychoses or affective switches.ConclusionOur meta-analysis suggests that repeated intranasal ketamine conducted a fast-onset antidepression effect in unipolar depression, while the mild and transient adverse effects were acceptable.Systematic Review RegistrationPROSPERO, CRD42020196856.

White matter hyperintensity volume and early-onset post-stroke depression in Thai older patients

ABSTRACTObjectivePost-stroke depression (PSD) is one of the most frequent psychiatric symptoms after a stroke event. The role of white matter hyperintensities (WMHs) associated with PSD in older patients remains unclear. This study aimed to examine the volume and location of white matter microstructure abnormalities among older patients with early-onset PSD.MethodsOlder (≥55 years) patients with acute cerebral infarction and hospitalized in King Chulalongkorn Memorial Hospital’s stroke unit from October 2019 to September 2020 were recruited. Participants were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) within three months after the onset of stroke. All patients had MRI scans. The brain images were segmented into four regions via left/right, frontal/dorsal plains. Two WMHs volume detections (visual rating vs. semi-automated WMHs volumetric detection) were employed on the fluid-attenuated inversion recovery images (FLAIR) for each segment. The study then investigated the association between WMHs volume and MADRS score with regression analysis.ResultsThe study included twenty-nine patients with acute stroke. Total WMHs volume and segmented regions were not statistically associated with the MADRS score. However, there was a trend in different WHMs volume of the left anterior segment between depressed and non-depressed groups (t-test 2.058, p = 0.055). Further, demographic and clinical data showed no association with depressive symptoms.ConclusionThe volume of WHMs might not contribute to the development of early-onset PSD in older patients. This study showed a potential of a quantitative MRI analysis in clinical practice. Further investigation with a larger group of patients is needed.

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

IntroductionMajor depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%–60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity.Methods and analysisThis is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients’ self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12.Ethics and disseminationThis protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226—EK 11) and by the relevant federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences.Trial registration numbersNCT04301271, DRKS00021119, EudraCT 2018-002947-27.

Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials

Background At ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR–gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. Methods Participants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery–Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. Results In the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected. Conclusions Variation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect. Trial Registration NCT02417064 and NCT02418585; www.clinicaltrials.gov

Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms

Context Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. Objective To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. Design and Intervention Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. Setting Academic medical center. Patients Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3). Main Outcome Measure Depressive symptoms (MADRS score). Results During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (β = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; β = −2.62 [95% CI, −4.52 to −0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events. Conclusions Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.

A cross sectional study of prevalence of depression among patients with cerebrovascular accident

Background: Depression is one of the most common neuropsychiatric condition in patients with stroke. Early identification of depression for stroke patients can improve the outcome leading to better quality of life. Prevalence and determinants of post stroke depression are highly variable and there is paucity of data in Indian literature.Methods: This cross-sectional study was conducted at neurology department of Saveetha Medical College, Chennai. All patients with history of stroke within past one month attending neurology department who fulfilled the inclusion criteria were taken up for the study after getting consent. Neurological examination and CT brain findings were noted with the site of lesion. All patients were evaluated for depression using ICD 10 criteria. MADRS score was used to assess the severity of depression. Chi square was used for statistical analysis.Results: The mean age of subjects in the study was 56.54±10.82 years. The prevalence of depression among patients with stroke in our study was 75.8%. Among classifying those with depression based on severity using MADRS score, 35% had mild depression and 65% had moderate depression. There was no severe depression in our sample. There was no statistically significant difference between prevalence of depression based on side of lesion.Conclusions: In this study the prevalence of depression among patients with cerebrovascular accident was found to be 75.8%. From this study we learn that the prevalence of depression in patients with stroke is high and this shows that regular screening of patients with stroke for depression might help in earlier detection and management of depression.

Functional connectivity predictors of acute depression treatment outcome

ABSTRACTFew studies have examined functional connectivity (FC) patterns using functional magnetic resonance imaging (fMRI) to predict outcomes in late-life depression. We hypothesized that FC within and between frontal and limbic regions would be associated with 12-week depression outcome in older depressed adults. Seventy-one subjects with major depression were enrolled in the study. A study geriatric psychiatrist performed a clinical interview and completed a Montgomery-Åsberg Depression Rating Scale (MADRS). All study participants were free of medication at baseline and had a brain fMRI scan. Using a regions of interest (ROI) atlas (including 164 ROIs), we conducted ROI-to-ROI resting-state FC analyses for each participant. In terms of treatment participants were offered sertraline initially, although in this naturalistic study, other medications were also prescribed. Subjects were evaluated every 2 weeks up to 12 weeks by the study psychiatrist, who followed a flexible, clinically based medication dosing schedule. Multivariate regression analysis was used to examine correlation between change of MADRS score over 12 weeks and baseline FC between brain regions, controlling for age, gender, mean head motion, and baseline MADRS. We found greater FC between the left inferior frontal gyrus pars triangularis and the left frontal eye field and FC of these two regions with a number of brain regions related to reward, salience, and sensorimortor function were correlated with change in MADRS score over 12 weeks. Our results highlight the important role of between inner speech-reward, attention-salience, and attention-sensorimotor network synchronization in predicting acute treatment response in late-life depression.

Effects of Valproate and Fluoxetine Combination on YMRS and MADRS Sores in Continuation Phase Treatment of Bipolar Disorder

Valproate is the most common drug to use in bipolar disorder in Indonesia and the only mood stabilizer drug in national formulary. Combination of valproate and fluoxetine are the most used combination in bipolar disorder therapy in Bhayangkara Hospital, Kediri. However, this combination has been controversial because of its risk of triggering mania or hipomania episode in 12 months. The aim of this study was to analyze mood change symptoms with YMRS and MADRS scale after treatment of valproate and fluoxetine combination in continuation phase treatment of bipolar disorder. This cross-sectional, observational study was conducted in psyciatry clinic in Bhayangkara Hospital Kediri between August 2016-October 2016 on 15 patients in YMRS. MADRS questionnaire was filled by physician before treatment and after 8 weeks treatments. Within 8 weeks, mean YMRS score changed from 1.4 to 1.26 (p>0.05). Whereas, mean MADRS score changed from 31.8 to 10.93 (p<0.05) after 8 weeks. There was no significant different in YMRS score between pre- and post-treatment, but there was significant different in MADRS score after treatment.