A Systematic Review on the Efficacy of Intravenous Racemic Ketamine for Bipolar Depression.

BACKGROUND: Ketamine, a glutamate N-methyl-d-aspartate receptor antagonist, has shown rapid antidepressant effects in treatment-resistant depression. We conducted a systematic review of studies evaluating the efficacy of intravenous ketamine augmentation in treatment-resistant depression patients with bipolar disorder. METHODS: Major databases were searched for open-label and randomized controlled trials (RCT). Two independent reviewers screened and selected the studies that met the inclusion criteria. Studies were selected following the standard Cochrane methodology, and the findings are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Methodological quality of the included studies was assessed using standardized measures. RESULTS: A total of 1442 articles were screened. Five studies were included in the systematic review (3 RCTs and 2 open-label studies) enrolling 110 subjects (mean age, 45.54 ± 12.65 years; 68.18% female). All the RCTs and open-label studies showed improvement in depressions symptoms after receiving a single infusion of ketamine. Included studies also suggested improvement in suicidal ideation and anhedonia after ketamine infusion. Dissociation and transient increase in blood pressure were the most common reported adverse effects with ketamine. Ketamine infusions did not increase mania symptoms. CONCLUSIONS: Limited data show efficacy and feasibility of intravenous racemic ketamine in treatment-resistant bipolar depression. Further studies with larger sample size are required to strengthen the evidence.

Galantamine-memantine combination superior to donepezil-memantine combination in Alzheimer's disease: critical dissection with an emphasis on kynurenic acid and mismatch negativity.

BACKGROUND: The donepezil-memantine combination is a US Food and Drug Administration (FDA)-approved medication to treat Alzheimer's disease (AD). Galantamine is superior to donepezil because it is a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7nAChR). Although galantamine and memantine are both FDA approved for the treatment of AD, the combination is still underutilized in clinical practice. AIM: The objective of this review was to critically examine the mechanisms by which the galantamine-memantine combination may be superior to the donepezil-memantine combination in AD by targeting the cholinergic-nicotinic and glutamatergic systems concurrently. METHOD: PubMed and Google Scholar were searched using the keywords Alzheimer's disease, cholinergic, glutamatergic, α7nAChR, N-methyl-D-aspartate (NMDA) receptors, donepezil, galantamine, memantine, clinical trials, and biomarkers. RESULTS: AD is associated with several biomarkers such as kynurenine pathway (KP) metabolites, mismatch negativity (MMN), brain-derived neurotrophic factor (BDNF), and oxidative stress. In several preclinical studies, cognitive impairments significantly improved with the galantamine-memantine combination compared to either medication alone. Synergistic benefits were also seen with the combination. In a randomized controlled trial (RCT) in prodrome AD, cognition significantly improved with the galantamine-memantine combination compared to galantamine alone; cognition declined after galantamine was discontinued. However, in an RCT in AD, cognition did not significantly improve with the galantamine-memantine combination compared to galantamine alone. In a retrospective study in AD, the galantamine-memantine combination significantly improved cognition compared to the donepezil-memantine combination. Galantamine and memantine via the α7nACh and NMDA receptors can counteract the effects of kynurenic acid and enhance MMN and BDNF. CONCLUSION: Future studies with the galantamine-memantine combination with KP metabolites, MMN, and BDNF as biomarkers are warranted. Positive RCTs in AD may lead to FDA approval of the combination, resulting in greater utilization in clinical practice. In the meantime, clinicians may continue to use the galantamine-memantine combination to treat patients with AD.

Early-Life Trauma in Hospitalized Patients With Mood Disorders and Its Association With Clinical Outcomes.

BACKGROUND: The prevalence of childhood trauma and its impact on clinical outcomes in hospitalized patients with mood disorders is unknown. We studied the frequency of childhood trauma among inpatient adults with mood disorders and its association with clinical outcomes. METHODS: Patients admitted to our hospital with a primary diagnosis of mood disorders completed the short form of the Early Trauma Inventory-Self-Report (ETISR-SF), the Sheehan Disability Scale, and the Clinician-Rated Dimensions of Psychosis Symptom Severity scale. A regression model adjusted for multiple comparisons was used to examine the association between scores on the ETISR-SF and clinical outcomes. RESULTS: Subjects were 167 patients, all of whom reported ≥1 types of childhood trauma: 90% general trauma, 75% physical abuse, 71% emotional abuse, 50% sexual abuse, and 35% all 4 types of abuse. The subtypes of abuse did not differ by sex or race. Diagnoses in the sample were bipolar disorder 56%, major depressive disorder 24%, schizoaffective disorder 14%, and substance-induced mood disorder 5%. The mean age in the sample was 35±11.5 years, 53% were male, and 64% also had substance abuse disorders. Higher scores on the ETISR-SF were associated with longer hospital stays [odds ratio (OR)=1.13; 95% confidence interval (CI), 1.05-1.22], and greater disruption of work/school life (OR=1.12; 95% CI, 1.04-1.21). There was also a trend for higher ETISR-SF scores to be associated with more severe psychotic symptoms (OR=1.13; 95% CI, 1.01-1.27) and more disruption in social (OR=1.14; 95% CI, 1.06-1.22) and family life (OR=1.09; 95% CI, 1.02-1.17). CONCLUSION: Childhood trauma was reported by all of the 167 patients, with general trauma the most common and approximately half reporting sexual abuse. Childhood trauma was associated with poor clinical outcomes. Early recognition of trauma and trauma-related therapeutic interventions may improve outcomes.

Efficacy of Prazosin in Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis.

OBJECTIVE: To consolidate the evidence from the literature to evaluate the role of prazosin in the treatment of posttraumatic stress disorder (PTSD). DATA SOURCES: Major databases, including PubMed, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO, and Scopus, were searched through August 2015 for studies reporting the role of prazosin in the treatment of PTSD with no language constraints. Keywords included (PTSD OR posttraumatic stress OR posttraumatic stress OR nightmares) AND prazosin. STUDY SELECTION: Of 402 screened articles, 6 studies were included in the systematic review and meta-analysis. DATA EXTRACTION: Two reviewers independently extracted relevant data (study characteristics, type of intervention, outcome measures, and follow-up) from the included studies using a standardized data extraction form. Only randomized controlled trials comparing prazosin to a placebo or control group in patients with PTSD were included. RESULTS: The patients with PTSD receiving prazosin showed significant improvement in nightmares (standardized mean difference [SMD] = 1.01; 95% CI, 0.72-1.30), overall PTSD symptoms (SMD = 0.77; 95% CI, 0.48-1.06), and clinical global improvement (SMD = 0.94; 95%, CI 0.6-1.29) compared to the placebo/control group. Prazosin improved sleep quality (SMD = 0.87; 95% CI, 0.55-1.19), hyperarousal symptoms (SMD = 1.04; 95% CI, 0.23-1.84), dream content (SMD = 1.33; 95% CI, 0.69-1.97), and total sleep time (60.98 minutes; 95% CI, 18.69-103.26). Prazosin was fairly well tolerated. Minor side effects were reported, which were similar between the prazosin and placebo groups. CONCLUSIONS: This study suggests that prazosin improves nightmares and overall PTSD symptoms including hyperarousal, sleep disturbances, total sleep time, and sleep quality.

Role of Botulinum Toxin in Depression.

OBJECTIVE: The goal of this review was to consolidate the evidence concerning the efficacy of botulinum toxin type A (onabotulinumtoxinA) in depression. METHODS: We searched MEDLINE, EMBASE, Cochrane, and Scopus through May 5, 2014, for studies evaluating the efficacy of botulinum toxin A in depression. Only randomized controlled trials were included in the meta-analysis. A pooled mean difference in primary depression score, and pooled odds ratio for response and remission rate with 95% confidence interval (CI) were estimated using the random-effects model. Heterogeneity was assessed using Cochran Q test and χ statistic. RESULTS: Of the 639 articles that were initially retrieved, 5 studies enrolling 194 subjects (age 49±9.6 y) were included in the systematic review, and 3 randomized controlled trials enrolling 134 subjects were included in the meta-analysis. The meta-analysis showed a significant decrease in mean primary depression scores among patients who received botulinum toxin A compared with placebo (-9.80; 95% CI, -12.90 to -6.69) with modest heterogeneity between the studies (Cochran Q test, χ=70). Response and remission rates were 8.3 and 4.6 times higher, respectively, among patients receiving botulinum toxin A compared with placebo, with no heterogeneity between the studies. The 2 studies excluded from the meta-analysis also found a significant decrease in primary depression scores in patients after receiving botulinum toxin A. A few subjects had minor side effects, which were similar between the groups receiving botulinum toxin and those receiving placebo. CONCLUSIONS: This study suggests that botulinum toxin A can produce significant improvement in depressive symptoms and is a safe adjunctive treatment for patients receiving pharmacotherapy for depression. Future trials are needed to evaluate the antidepressant effect per se of botulinum toxin A and to further elucidate the underlying antidepressant mechanism of botulinum toxin A.

Mortality associated with anxiolytic and hypnotic drugs-A systematic review and meta-analysis.

BACKGROUND: Use of hypnotics or anxiolytic drugs is common and various studies have reported increased mortality with hypnotics or anxiolytic use. OBJECTIVE: To consolidate the evidence on mortality risk associated with hypnotics or anxiolytic use METHODS: Major databases were searched through April 2014 for studies reporting mortality risk associated with hypnotics or anxiolytics use. A pooled hazard ratio with 95% confidence interval was estimated using random-effects model. RESULTS: After screening 2188 articles, 25 studies (24 cohort, 1 case-control) enrolling 2,350,093 patients with 59% females (age 18-102 years) were included in the meta-analysis. Hypnotics or anxiolytic users had 43% higher risk of mortality than non-users (hazard ratio, 1.43; 95% confidence interval, [1.12, 1.84]). Eight studies reported risk estimates for each gender category and pooled results from these studies showed increased risk of mortality among men (hazard ratio = 1.60, 95% confidence interval = [1.29,1.99]) and women (hazard ratio = 1.68, 95% confidence interval = [1.38, 2.04]). Pooled results from 10 studies showed higher mortality among benzodiazepine users compared to non-users (hazard ratio = 1.60, 95% confidence interval = [1.03, 2.49]), while pooled results from five studies showed an increased risk of mortality with Z-drugs use although the effect could not reach statistical significance (hazard ratio = 1.73, 95% confidence interval = [0.95, 3.16]). Significant heterogeneity was observed in the analyses and the quality of included studies was good. CONCLUSION: This meta-analysis suggests that hypnotics or anxiolytics drugs use is associated with increased mortality and hence should be used with caution. Future studies focused on underlying mechanism of increased mortality with hypnotics or anxiolytics use are required.

Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis.

OBJECTIVE: To consolidate the evidence from the literature to evaluate the role of ketamine in the treatment of bipolar depression. METHODS: Major databases, including MEDLINE, EMBASE, Cochrane, and Scopus, were searched through October 2014, for studies reporting the role of ketamine in the treatment of bipolar depression. Only randomized controlled trials were included in the meta-analysis. We calculated standardized mean differences (SMDs) with SE for each study included in the meta-analysis. A random effect model was used to calculate the pooled SMDs. Heterogeneity was assessed using the Cochran Q test and I statistic. RESULTS: Of the 721 articles that were screened, 5 studies that enrolled a total of 125 subjects with bipolar depression (mean age, 44.6±4.3 y and 65.6% females) were included in the systematic review; 3 randomized controlled trials (69 subjects) were included in the meta-analysis. The meta-analysis showed significant improvement in depression among patients receiving a single dose of intravenous ketamine compared with those who received placebo (SMD=-1.01; 95% confidence interval, -1.37, -0.66; P<0.0001). The maximum improvement was observed 40 minutes after the ketamine infusion. No heterogeneity was observed between the studies (Cochran Q test P=0.38, I=0%). The 2 studies that were excluded from the meta-analysis also showed significant improvement in depression after ketamine therapy. Individual studies also reported improvement in anhedonia and suicidal ideation after ketamine therapy. None of the subjects had serious side effects, and the side effects were similar between the ketamine and placebo groups. CONCLUSIONS: This study suggests that ketamine is effective in treatment-resistant bipolar depression and may reduce suicidal ideation and anhedonia.

Involuntary detention: comparison of clinical practices of psychiatry residents and faculty.

OBJECTIVE: The objective of this study is to study if involuntary detention criteria in legal certificates filed by psychiatry residents and faculty psychiatrists are consistent with observations in clinical documentation. METHODS: Eighty-nine involuntarily hospitalized patients were retrospectively selected from medical records; eight patients were excluded due to change in involuntary status or immediate discharge on clinical grounds. Medical certificates filed by the residents and faculty psychiatrists were compared with clinical documentation of the same day for consistency in criteria for detention (substantial risk of harm to self or others and/or inability to care for self). RESULTS: Of 81 included patients, 38.3 % lacked sufficient documentation of clinical justification for involuntary hospitalization. The rate of inconsistency of documented clinical justification showed a greater trend among psychiatry residents compared to faculty psychiatrists (p = 0.069, not statistically significant). CONCLUSIONS: Inconsistency of documented clinical justification for involuntarily detention was higher among residents compared to faculty. There is a need for structured training and supervision of psychiatry residents as well as updated training for faculty psychiatrists with regard to involuntary detention procedures.

A prospective study of chronic obstructive pulmonary disease and the risk for mild cognitive impairment.

IMPORTANCE: Previous studies suggest cross-sectional associations between a diagnosis of chronic obstructive pulmonary disease (COPD) and mild cognitive impairment (MCI). However, few studies have assessed whether COPD, a potentially modifiable factor, is associated with an increased risk for MCI and whether the relation is specific to the type of MCI. OBJECTIVE: To investigate whether a diagnosis of COPD and duration of COPD are associated with an increased risk for incident MCI and MCI subtypes (amnestic MCI [A-MCI] and nonamnestic MCI [NA-MCI]). DESIGN, SETTING, AND PARTICIPANTS: A prospective population-based cohort from the Mayo Clinic Study on Aging. We included 1425 cognitively normal individuals aged 70 to 89 years who were randomly selected from Olmsted County, Minnesota, on October 1, 2004, using the medical records linkage system. At baseline and every 15 months thereafter, participants underwent assessment with a nurse interview, neurologic examination, and neuropsychological testing. A diagnosis of COPD was confirmed via medical record review. A baseline diagnosis of COPD and duration of COPD were examined as risk factors for MCI and MCI subtypes using Cox proportional hazards models and adjusting for demographic variables and medical comorbidities, with age as the time scale. EXPOSURE: A baseline diagnosis of COPD and duration of COPD. MAIN OUTCOMES AND MEASURES: Incident MCI, A-MCI, and NA-MCI. RESULTS: Of the 1425 participants with normal cognition at baseline, 370 developed incident MCI. The median duration of follow-up was 5.1 years (interquartile range, 3.8-5.4 years). A diagnosis of COPD significantly increased the risk for NA-MCI by 83% (hazard ratio, 1.83 [95% CI, 1.04-3.23]), but not of any MCI or A-MCI in multivariate analyses. We found a dose-response relationship such that individuals with COPD duration of longer than 5 years at baseline had the greatest risk for any MCI (hazard ratio, 1.58 [95% CI, 1.04-2.40]) and NA-MCI (2.58 [1.32-5.06]). CONCLUSIONS AND RELEVANCE: A diagnosis of COPD is associated with an increased risk for MCI, particularly NA-MCI. We have found a dose-response relationship between COPD duration and risk for MCI. These findings highlight the importance of COPD as a risk factor for MCI and may provide a substrate for early intervention to prevent or delay the onset and progression of MCI, particularly NA-MCI.

Involuntary detention: do psychiatrists clinically justify continuing involuntary hospitalization?

To elucidate disparities in clinical and legal documentation for patients admitted involuntarily to a county psychiatric hospital in Texas. The study sample comprised of 89 randomly selected patients, involuntarily hospitalized to our facility in September 2011. All patients met criteria for involuntary detention based on the legal documents filed by admitting psychiatrists. Electronic medical records were reviewed to assess if the clinical documentation from the same date when legal documents were filed; demonstrated criteria for involuntary detention (harm to self, harm to others, inability to care for self). A logistic regression model was used to assess the predictors of concordance between legal and clinical documentation of involuntary detention criteria. Of 89, 6 patients were made voluntary, while two were discharged within 24 h, thus removed from the analysis pool. Of 81, 31(38.2 %) patients lacked sufficient clinical documentation on medical records required for involuntary hospitalization. Patients, for whom detention was justified in clinical notes, were more likely to have single marital status, longer duration of hospitalization and they were more likely to undergo commitment for further inpatient mental health treatment. Our study found that involuntary detention of many patients based on the legal documents filed by admitting psychiatrists was not justified by the clinical documentation. This indicates that appropriate standards are not maintained when completing the medical certificates for involuntary detention. Maintaining appropriate standards may reduce the need for involuntary hospitalization, increase patient autonomy, and reduce resource utilization.

Hypothyroidism and risk of mild cognitive impairment in elderly persons: a population-based study.

IMPORTANCE: An association of clinical and subclinical hypothyroidism with mild cognitive impairment (MCI) has not been established. OBJECTIVE: To evaluate the association of clinical and subclinical hypothyroidism with MCI in a large population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, population-based study was conducted in Olmsted County, Minnesota. Randomly selected participants were aged 70 to 89 years on October 1, 2004, and were without documented prevalent dementia [CORRECTED]. A total of 2050 participants were evaluated and underwent in-person interview, neurologic evaluation, and neuropsychological testing to assess performance in memory, attention/executive function, and visuospatial and language domains. Participants were categorized by consensus as being cognitively normal, having MCI, or having dementia according to published criteria. Clinical and subclinical hypothyroidism were ascertained from a medical records linkage system. MAIN OUTCOMES AND MEASURES: Association of clinical and subclinical hypothyroidism with MCI. RESULTS: Among 1904 eligible participants, the frequency of MCI was 16% in 1450 individuals with normal thyroid function, 17% in 313 persons with clinical hypothyroidism, and 18% in 141 individuals with subclinical hypothyroidism. After adjusting for covariates (age, educational level, sex, apolipoprotein E ε4, depression, diabetes mellitus, hypertension, stroke, body mass index, and coronary artery disease) we found no significant association between clinical or subclinical hypothyroidism and MCI (odds ratio [OR], 0.99 [95% CI, 0.66-1.48] and 0.88 [0.38-2.03], respectively). No effect of sex interaction was seen on these effects. In stratified analysis, the odds of MCI with clinical and subclinical hypothyroidism among men was 1.02 (95% CI, 0.57-1.82) and 1.29 (0.68-2.44) and, among women, was 1.04 (0.66-1.66) and 0.86 (0.37-2.02), respectively. CONCLUSIONS AND RELEVANCE: In this population-based cohort of elderly people, neither clinical nor subclinical hypothyroidism was associated with MCI. Our findings need to be validated in a separate setting using the published criteria for MCI and confirmed in a longitudinal study.

Statins use and risk of depression: a systematic review and meta-analysis.

IMPORTANCE: Statin use has been associated with depression; however studies of the association between statin use and depression have yielded mixed results. OBJECTIVE: To determine whether statin use is associated with depression and to evaluate the evidence supporting this association. DATA SOURCES: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched through December 28, 2012. STUDY SELECTION: We included studies that evaluated exposure to statins, reported the development of depression, and relative risks or odds ratios (ORs) or provided data for their estimation. Two reviewers screened 981 abstracts independently using a standardized form, reviewed full text of 59 selected articles, and included 7 studies in this metaanalysis. DATA EXTRACTION AND SYNTHESIS: Study design, statin exposure, development of depression, and study quality were extracted by 2 independent reviewers. A pooled OR with 95% confidence interval (CI) was estimated using the random-effects model and heterogeneity was assessed using Cochran's Q test and the I(2) statistic. RESULTS: Seven observational studies (4 cohort, 2 nested case-control, and 1 cross-sectional) from 5 countries enrolling 9187 patients were included. Statin users were 32% less likely to develop depression than nonusers (adjusted OR, 0.68; 95% CI, 0.52-0.89). Modest heterogeneity was observed between the studies (I(2)=55%, P=0.01), which could be accounted for by one study, exclusion of which removed the heterogeneity (P=0.40, I(2)=2%) and further strengthened the antidepressant effect of statin (adjusted OR, 0.63; 95% CI, 0.43-0.93). Heterogeneity could not be explained by study design or study population. The quality of supporting evidence was fair. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis suggests that statin use is associated with lower risk for depression. However, higher-quality studies are needed to confirm the magnitude of this association.

Association of mediterranean diet with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVE: To conduct a systematic review of all studies to determine whether there is an association between the Mediterranean diet (MeDi) and cognitive impairment. METHODS: We conducted a comprehensive search of the major databases and hand-searched proceedings of major neurology, psychiatry, and dementia conferences through November 2012. Prospective cohort studies examining the MeDi with longitudinal follow-up of at least 1 year and reporting cognitive outcomes (mild cognitive impairment [MCI] or Alzheimer's disease [AD]) were included. The effect size was estimated as hazard-ratio (HR) with 95% confidence intervals (CIs) using the random-effects model. Heterogeneity was assessed using Cochran's Q-test and I2-statistic. RESULTS: Out of the 664 studies screened, five studies met eligibility criteria. Higher adherence to the MeDi was associated with reduced risk of MCI and AD. The subjects in the highest MeDi tertile had 33% less risk (adjusted HR = 0.67; 95% CI, 0.55-0.81; p < 0.0001) of cognitive impairment (MCI or AD) as compared to the lowest MeDi score tertile. Among cognitively normal individuals, higher adherence to the MeDi was associated with a reduced risk of MCI (HR = 0.73; 95% CI, 0.56-0.96; p = 0.02) and AD (HR = 0.64; 95% CI, 0.46-0.89; p = 0.007). There was no significant heterogeneity in the analyses. CONCLUSIONS: While the overall number of studies is small, pooled results suggest that a higher adherence to the MeDi is associated with a reduced risk of developing MCI and AD, and a reduced risk of progressing from MCI to AD. Further prospective-cohort studies with longer follow-up and randomized controlled trials are warranted to consolidate the evidence. Systematic review registration number: PROSPERO 2013: CRD42013003868.

Chronic obstructive pulmonary disease and association with mild cognitive impairment: the Mayo Clinic Study of Aging.

OBJECTIVE: To investigate the association of chronic obstructive pulmonary disease (COPD) with mild cognitive impairment (MCI) and MCI subtype: amnestic MCI and nonamnestic MCI, in a population-based study of elderly patients. PATIENTS AND METHODS: Participants included 1927 individuals aged 70 to 89 years enrolled in the population-based Mayo Clinic Study of Aging. Participants were evaluated by using a nurse assessment, neurological evaluation, and neuropsychological testing, and the diagnosis of MCI was made by a consensus panel according to the standardized criteria. Chronic obstructive pulmonary disease was identified by the review of medical records. The study was conducted from October 1, 2004, through July 31, 2007. The associations of COPD and disease duration with MCI and its subtypes were evaluated by using logistic regression models adjusted for potential covariates. RESULTS: Of 1927 participants, 288 had COPD (men vs women: 18% vs 12%; P<.001). As compared with patients without COPD, patients with COPD had a higher prevalence of MCI (27% vs 15%; P<.001). The odds ratio (OR) for MCI was almost 2 times higher in patients with COPD than in those without (OR, 1.87; 95% CI, 1.34-2.61), with a similar effect in men and women. The OR for MCI increased from 1.60 (95% CI, 0.97-2.57) in patients with a COPD duration of 5 years or less to 2.10 (95% CI, 1.38-3.14) in patients with a COPD duration of more than 5 years. CONCLUSION: This population-based study suggests that COPD is associated with increased odds of having MCI and its subtypes. There was a dose-response relationship with the duration of COPD after controlling for the potential covariates.

Endovascular therapy for acute ischemic stroke: a systematic review and meta-analysis.

OBJECTIVE: To consolidate the evidence from randomized trials for the use of endovascular therapy (ET) in patients with acute ischemic stroke. METHODS: We searched major databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus) from their inception to February 12, 2013, for randomized trials evaluating the efficacy of ET compared with standard of care for acute ischemic stroke. Pooled absolute and relative risk estimates were synthesized by using a random-effects model. Heterogeneity was assessed by using Q statistic and I(2) statistic. Subset analysis was performed for patients with severe stroke (National Institutes of Health Stroke Scale score ≥20). The study was conducted from January 15, 2013 to April 30, 2013. RESULTS: Of the 1252 retrieved articles, 5 randomized trials enrolling 1197 patients with acute ischemic stroke were included. Seven hundred eleven patients received ET, and 486 received intravenous (IV) tissue plasminogen activator. There was no significant improvement in any of the outcomes in patients receiving ET compared with those receiving IV thrombolysis. On subgroup analysis, ET was found to have better outcomes in patients with severe stroke (National Institutes of Health Stroke Scale score ≥20), showing a dose-response gradient and improving excellent, good, and fair outcomes by an additional 4%, 7%, and 13%, respectively, compared with IV thrombolysis. CONCLUSION: Overall, ET is not superior to IV thrombolysis for acute ischemic strokes (level B recommendation). However, ET showed promise and improved outcomes in patients with severe strokes, but the evidence is limited due to sample size. There is a need for further trials evaluating the role of ET in this high-risk group.

Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials.

OBJECTIVE: To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH). METHODS: We searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies. RESULTS: Seven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg (p = 0.65) and the mean change in mean arterial pressure from supine to standing was -1.7 mmHg (p = 0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg (p < 0.001). A significant improvement was seen in patients' and investigators' global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30-1.09; p < 0.001] and 0.80 [95 % CI 0.76-0.85; p < 0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias. CONCLUSION: There is insufficient and low quality evidence to support the use of midodrine for OH.