DOACs for Older adults with Atrial Fibrillation and Falls: Results from the prospective single-centre DOAFF study.

INTRODUCTION: Falls are one of the most fearsome events in anticoagulated older adults. The evidence concerning safety of direct oral anticoagulants (DOACs) in falling elderly patients with atrial fibrillation (AF) is still limited. METHODS: We prospectively enrolled consecutive anticoagulant-naïve patients aged 65 years and older, starting anticoagulation with DOACs for AF. The study cohort was stratified in fallers vs. non-fallers, according to the occurrence of at least one fall during the 2-year follow-up and bleeding outcomes were evaluated. RESULTS: We enrolled 524 consecutive patients. Mean age was 80.8 years and they were mostly women (54.0%). Among the study cohort, 148 patients (28.2%) presented at least one fall episode during the study period. After the adjustment for potential confounders, no difference was found between fallers and non-fallers for all the study outcomes: major bleeding [HR: 1.04 (95%CI: 0.58-1.85)], intracranial haemorrhage [HR: 1.63 (95%CI: 0.69-3.80)], clinically relevant non-major bleeding [HR: 1.21 (95%CI: 0.83-1.76)], and all-cause death [HR: 1.51 (95%CI: 0.85-2.69)]. The presence of a prior cerebrovascular event [HR: 2.27 (95%CI: 1.12-4.62); p-value: 0.02] and polypharmacy [HR: 1.60 (95%CI: 1.08-2.39); p-value: 0.02] were the main drivers for major and clinically relevant non-major bleedings, respectively. CONCLUSIONS: Falls in an anticoagulant-naïve population aged 65 years and over starting a DOAC for AF do not increase the bleeding risk. Thus, the presence of falls should not discourage clinicians from prescribing DOACs also in this subset of patients.

The impact of COVID-19 on myocardial infarctions, strokes and out-of-hospital cardiopulmonary arrests: an observational retrospective study on time-sensitive disorders in the Friuli Venezia Giulia region (Italy).

The COVID-19 global pandemic has changed considerably the way time-sensitive disorders are treated. Home isolation, people's fear of contracting the virus and hospital reorganisation have led to a significant decrease in contacts between citizens and the healthcare system, with an expected decrease in calls to the Emergency Medical Services (EMS) of the Friuli-Venezia Giulia (FVG) region. However, mortality in clinical emergencies like acute ST-elevation myocardial infarction (STEMI), stroke and out-of-hospital cardiopulmonary arrest (OHCA) remained high. An observational retrospective cross-sectional study was carried out in FVG, taking into account the period between March 1, 2020, and May 31, 2020, the first wave of the COVID-19 pandemic, and comparing it with the same period in 2019. The flow of calls to the EMS was analysed and COVID-19 impact on time-sensitive disorders (STEMIs, ischemic strokes and OHCPAs) was measured in terms of hospitalisation, treatment and mortality. Despite a -8.01% decrease (p value ˂0.001) in emergency response, a 10.89% increase in calls to the EMS was observed. A lower number of advanced cardiopulmonary resuscitations (CPR) (75.8 vs 45.2%, p=0.000021 in April) and ROSC (39.1 vs 11.6%, p=0.0001 in April) was remarked, and survival rate dropped from 8.5 to 5%. There were less strokes (-27.5%, p value=0.002) despite a more severe onset of symptoms at hospitalisation with NHISS˃10 in 38.47% of cases. Acute myocardial infarctions decreased as well (-20%, p value=0.05), but statistical significances were not determined in the variables considered and in mortality. Despite a lower number of emergency responses, the number of calls to the EMS was considerably higher. The number of cardiac arrests treated with advanced CPR (ALS) was lower, but mortality was higher. The number of strokes decreased as well, but at the time of hospitalisation the clinical picture of the patient was more severe, thus affecting the outcome when the patient was discharged. Finally, STEMI patients decreased; however, no critical issues were observed in the variables taken into account, neither in terms of response times nor in terms of treatment times.

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

BACKGROUND: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke. METHODS: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies. RESULTS: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers. CONCLUSIONS: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.

Predictors of Treatment Resistance Across Different Clinical Subtypes of Depression: Comparison of Unipolar vs. Bipolar Cases.

OBJECTIVE: Treatment-resistant depression (TRD) and treatment-resistant bipolar depression (TRBD) poses a significant clinical and societal burden, relying on different operational definitions and treatment approaches. The detection of clinical predictors of resistance is elusive, soliciting clinical subtyping of the depressive episodes, which represents the goal of the present study. METHODS: A hundred and thirty-one depressed outpatients underwent psychopathological evaluation using major rating tools, including the Hamilton Rating Scale for Depression, which served for subsequent principal component analysis, followed-up by cluster analysis, with the ultimate goal to fetch different clinical subtypes of depression. RESULTS: The cluster analysis identified two clinically interpretable, yet distinctive, groups among 53 bipolar (resistant cases = 15, or 28.3%) and 78 unipolar (resistant cases = 20, or 25.6%) patients. Among the MDD patients, cluster "1" included the following components: "Psychic symptoms, depressed mood, suicide, guilty, insomnia" and "genitourinary, gastrointestinal, weight loss, insight". Altogether, with broadly defined "mixed features," this latter cluster correctly predicted treatment outcome in 80.8% cases of MDD. The same "broadly-defined" mixed features of depression (namely, the standard Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition-DSM-5-specifier plus increased energy, psychomotor activity, irritability) correctly classified 71.7% of BD cases, either as TRBD or not. LIMITATIONS: Small sample size and high rate of comorbidity. CONCLUSIONS: Although relying on different operational criteria and treatment history, TRD and TRBD seem to be consistently predicted by broadly defined mixed features among different clinical subtypes of depression, either unipolar or bipolar cases. If replicated by upcoming studies to encompass also biological and neuropsychological measures, the present study may aid in precision medicine and informed pharmacotherapy.

Prominent autistic traits and subthreshold bipolar/mixed features of depression in severe anorexia nervosa

Objective: Autistic traits are associated with a burdensome clinical presentation of anorexia nervosa (AN), as is AN with concurrent depression. The aim of the present study was to explore the intertwined association between complex psychopathology combining autistic traits, subthreshold bipolarity, and mixed depression among people with AN. Method: Sixty patients with AN and concurrent major depressive episode (mean age, 22.2±7 years) were cross-sectionally assessed using the Autism-Spectrum Quotient test (AQ-test), the Hamilton depression scales for depression and anxiety, the Young Mania Rating Scale (YMRS), the Hypomania-Checklist-32 (HCL-32), second revision (for subthreshold bipolarity), the Brown Assessment and Beliefs Scale (BABS), the Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS), and the Eating Disorder Examination Questionnaire (EDE-Q). Cases were split into two groups depending on body mass index (BMI): severe AN (AN+) if BMI < 16, not severe (AN-) if BMI ≥ 16. Results: The "subthreshold bipolarity with prominent autistic traits" pattern correctly classified 83.6% of AN patients (AN+ = 78.1%; AN- = 91.3%, Exp(B) = 1.391). AN+ cases showed higher rates of positive scores for YMRS items 2 (increased motor activity-energy) and 5 (irritability) compared to AN- cases. Conclusions: In our sample, depressed patients with severe AN had more pronounced autistic traits and subtly mixed bipolarity. Further studies with larger samples and prospective follow-up of treatment outcomes are warranted to replicate these findings.

Prevalence and correlates of major depressive disorder, bipolar disorder and schizophrenia among nursing home residents without dementia: systematic review and meta-analysis.

BACKGROUND: The elderly population and numbers of nursing homes residents are growing at a rapid pace globally. Uncertainty exists regarding the actual rates of major depressive disorder (MDD), bipolar disorder and schizophrenia as previous evidence documenting high rates relies on suboptimal methodology. AIMS: To carry out a systematic review and meta-analysis on the prevalence and correlates of MDD, bipolar disorder and schizophrenia spectrum disorder among nursing homes residents without dementia. METHOD: Major electronic databases were systematically searched from 1980 to July 2017 for original studies reporting on the prevalence and correlates of MDD among nursing homes residents without dementia. The prevalence of MDD in this population was meta-analysed through random-effects modelling and potential sources of heterogeneity were examined through subgroup/meta-regression analyses. RESULTS: Across 32 observational studies encompassing 13 394 nursing homes residents, 2110 people were diagnosed with MDD, resulting in a pooled prevalence rate of 18.9% (95% CI 14.8-23.8). Heterogeneity was high (I2 = 97%, P≤0.001); no evidence of publication bias was observed. Sensitivity analysis indicated the highest rates of MDD among North American residents (25.4%, 95% CI 18-34.5, P≤0.001). Prevalence of either bipolar disorder or schizophrenia spectrum disorder could not be reliably pooled because of the paucity of data. CONCLUSIONS: MDD is highly prevalent among nursing homes residents without dementia. Efforts towards prevention, early recognition and management of MDD in this population are warranted.

Prominent autistic traits and subthreshold bipolar/mixed features of depression in severe anorexia nervosa.

OBJECTIVE: Autistic traits are associated with a burdensome clinical presentation of anorexia nervosa (AN), as is AN with concurrent depression. The aim of the present study was to explore the intertwined association between complex psychopathology combining autistic traits, subthreshold bipolarity, and mixed depression among people with AN. METHOD: Sixty patients with AN and concurrent major depressive episode (mean age, 22.2±7 years) were cross-sectionally assessed using the Autism-Spectrum Quotient test (AQ-test), the Hamilton depression scales for depression and anxiety, the Young Mania Rating Scale (YMRS), the Hypomania-Checklist-32 (HCL-32), second revision (for subthreshold bipolarity), the Brown Assessment and Beliefs Scale (BABS), the Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS), and the Eating Disorder Examination Questionnaire (EDE-Q). Cases were split into two groups depending on body mass index (BMI): severe AN (AN+) if BMI < 16, not severe (AN-) if BMI ≥ 16. RESULTS: The "subthreshold bipolarity with prominent autistic traits" pattern correctly classified 83.6% of AN patients (AN+ = 78.1%; AN- = 91.3%, Exp(B) = 1.391). AN+ cases showed higher rates of positive scores for YMRS items 2 (increased motor activity-energy) and 5 (irritability) compared to AN- cases. CONCLUSIONS: In our sample, depressed patients with severe AN had more pronounced autistic traits and subtly mixed bipolarity. Further studies with larger samples and prospective follow-up of treatment outcomes are warranted to replicate these findings.

The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications.

The re-emergence (i.e. 'breakthrough') of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients.

The identification of biomarkers predicting acute and maintenance lithium treatment response in bipolar disorder: A plea for further research attention.

The prediction of acute and maintenance lithium treatment response carries major clinical and neurobiological implications, warranting systematic review. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant review searched major electronic databases from inception until December 2017 for studies documenting a clinical diagnosis of bipolar disorder (BD) made according to the mainstream diagnostic manuals and confirmed by a structured interview. Eligible studies allowed a quantitative comparison of endpoint vs baseline mean values of a given biomarker, regardless of the mood phase of patients with BD, and the disorder was assessed for severity using validated rating tool(s). Owing to the purposely applied stringent selection criteria, 16 acute and 12 maintenance studies could be included. The anticipated publication bias limited the chances of reportable generalizable findings, hindering a side-by-side comparison of different records across varying biomarkers and subsequent meta-analyses. The PRISMA approach was nonetheless preferred; it aimed at enhancing the homogeneity of the included results and minimizing the chances of "apples and oranges" with respect to the present research theme. The present critical review confirms the need for future research to specifically assess either pretreatment and/or posttreatment putative biomarkers of patients with BD and treated with lithium.

Clinical and psychopathological features associated with treatment-emergent mania in bipolar-II depressed outpatients exposed to antidepressants.

BACKGROUND: Treatment-emergent affective switch (TEAS), including treatment-emergent mania (TEM), carry significant burden in the clinical management of bipolar depression, whereas the use of antidepressants raises both efficacy, safety and tolerability concerns. The present study assesses the prevalence and clinical correlates of TEM in selected sample of Bipolar Disorder (BD) Type-II (BD-II) acute depression outpatients. METHODS: Post-hoc analysis of the clinical and psychopathological features associated with TEM among 91 BD-II depressed outpatients exposed to antidepressants. RESULTS: Second-generation antipsychotics (SGA) (p = .005), lithium (≤ .001), cyclothymic/irritable/hyperthymic temperaments (p = ≤ .001; p = .001; p = .003, respectively), rapid-cycling (p = .005) and depressive mixed features (p = .003) differed between TEM+ cases vs. TEM- controls. Upon multinomial logistic regression, the accounted psychopathological features correctly classified as much as 88.6% of TEM+ cases (35/91 overall sample, or 38.46% of the sample), yet not statistically significantly [Exp(B) = .032; p = ns]. Specifically, lithium [B = - 2.385; p = .001], SGAs [B = - 2.354; p = .002] predicted lower rates of TEM+ in contrast to the number of lifetime previous psychiatric hospitalizations [B = 2.380; p = .002], whereas mixed features did not [B = 1.267; p = ns]. LIMITATIONS: Post-hoc analysis. Lack of systematic pharmacological history record; chance of recall bias and Berkson's biases. Permissive operational criterion for TEM. Relatively small sample size. CONCLUSIONS: Cyclothymic temperament and mixed depression discriminated TEM+ between TEM- cases, although only lithium and the SGAs reliably predicted TEM+/- grouping. Larger-sampled/powered longitudinal replication studies are warranted to allow firm conclusions on the matter, ideally contributing to the identification of clear-cut sub-phenotypes of BD towards patient-tailored-pharmacotherapy.

Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis.

BACKGROUND: Treatment-emergent mania (TEM) represents a common phenomenon inconsistently reported across primary studies, warranting further assessment. METHODS: A systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were conducted. Major electronic databases were searched from inception to May 2017 to assess the incidence and prevalence rates and clinical features associated with manic switch among bipolar depressed patients receiving antidepressants, using meta-regression and subgroup analysis. RESULTS: Overall, 10 098 depressed patients with bipolar disorder (BD) across 51 studies/arms were included in the quantitative analysis. The cumulative incidence of cases (TEM+ ) among 4767 patients with BD over 15 retrospective studies was 30.9% (95% confidence interval [CI] 19.6-45.0%, I2  = 97.9%). The cumulative incidence of TEM+ among 1929 patients with BD over 12 prospective open studies was 14.4% (95% CI 7.4-26.1%, I2  = 93.7%). The cumulative incidence of TEM+ among 1316 patients with BD over 20 randomized controlled trials (RCTs) was 11.8% (95% CI 8.4-16.34%, I2  = 73.46%). The pooled prevalence of TEM+ among 2086 patients with BD over four cross-sectional studies was 30.9% (95% CI 18.1-47.4%, I2  = 95.6%). Overall, concurrent lithium therapy predicted the lowest TEM rates. Inconsistent operational definitions of TEM were recorded, and the lack of information about age, sex, co-occurring anxiety, and other clinically relevant moderators precluded further stratification of the results. CONCLUSIONS: Rates of TEM vary primarily depending on study setting, which is concordant with the high degree of heterogeneity of the included records. Forthcoming RCT studies should adopt consistent operational definitions of TEM and broaden the number of moderators, in order to contribute most effectively to the identification of clear-cut sub-phenotypes of BD and patient-tailored pharmacotherapy.

Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician's perspective.

INTRODUCTION: Bipolar disorder (BD) is a considerable burden to the affected individual. The need for novel drug targets and improved drug design (DD) in BD is therefore clear. Areas covered: The following article provides a brief, narrative, clinician-oriented overview of the most promising novel pharmacological targets for BD along with a concise overview regarding the general DD process and the unmet needs relevant to BD. Expert opinion: A number of novel potential drug targets have been investigated. With the notable exception of the kynurenine pathway, available evidence is too scarce to highlight a definitive roadmap for forthcoming DD in BD. BD itself may present with different facets, as it is a polymorphic clinical spectrum. Therefore, promoting clinical-case stratification should be based on precision medicine, rather than on novel biological targets. Furthermore, the full release of raw study data to the scientific community and the development of uniform clinical trial standards (including more realistic outcomes) should be promoted to facilitate the DD process in BD.

Correlation between ADAMTS13 activity and neurological impairment in acute thrombotic microangiopathy patients.

Differential diagnosis between thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMA) is usually difficult because of frequently overlapping clinical presentations. Severely depressed ADAMTS13 activity (<10 %) seems distinctive for TTP because of its pathogenetic role. However a long debate exists in the literature about its sensibility and specificity. Our aim was to search for clinical differences between TMA patients referred to our laboratory, comparing them for protease activity <10 versus ≥10 %. ADAMTS13 activity ≥10 % patients (n = 73) showed a higher prevalence of drug- (p = 0.005) and cancer-associated (p < 0.001) TMA. Mean platelet count and renal dysfunction prevalence was lower (p < 0.001), while neurological impairment was more frequent (p = 0.001) in the <10 % ADAMTS13 activity group (n = 109), confirming previous literature findings. When taken neurological manifestations singularly, epilepsy (p = 0.04), focal motor deficit (p < 0.001) and cranial nerve palsy (p = 0.007) were more frequent in the <10 % activity group. In our case series, a <10 % ADAMTS13 activity depicts a group of patients with clinical features similar to TTP patients. Focal motor impairment or epileptic manifestations could further address toward a TTP diagnosis. Studies about treatment efficacy and follow-up are advised to determine whether laboratory findings can guide therapeutic decisions.

Are Early Seizures Predictive of Epilepsy after a Stroke? Results of a Population-Based Study.

BACKGROUND: In addition to determining the cumulative incidence and risk factors for early seizures (ES), late seizures (LS) and post stroke epilepsy (PSE), we aimed at checking if ES represented a risk factor for epilepsy and if early treatment after ES prevented the occurrence of subsequent seizures. METHODS: This study was part of a 2-year prospective community-based registry of all cerebrovascular events in the district of Udine (153,312 inhabitants), North-Eastern Italy, between April 1, 2007 and March 31, 2009. People with transient ischemic attacks (TIAs) were excluded from this study. RESULTS: In all, 782 cases of stroke (79.28% ischemic, 14.83% hemorrhagic, 3.20% subarachnoid hemorrhage and 2.69% undetermined) were identified. The incidence of ES, LS and PSE was 5.10, 3.14 and 2.22%, respectively. Intracerebral hemorrhage, subarachnoid hemorrhage, stroke of undetermined origin and hyponatremia, represented risk factors for ES (p < 0.05). Among ischemic strokes, ES risk factors were hyponatremia (p = 0.024) and hemorrhagic transformation (p = 0.046). LS risk factors were younger age (p = 0.004) and cortical location of stroke (p = 0.004). Within ischemic strokes, LS risk factors were younger age (p = 0.020) and cortical location (p < 0.0001). Within intracerebral hemorrhages, the only risk factor for LS was the presence of a previous ES (p = 0.017). PSE risk factors were the same as for LS. CONCLUSIONS: All acute conditions related to the occurrence of stroke are implicated in the pathogenesis of ES, which becomes a risk factor for LS only in the setting of intracerebral hemorrhages. Therefore, early antiepileptic treatment is needed only in this situation.