Fatigue Symptoms Associated With COVID-19 in Convalescent or Recovered COVID-19 Patients; a Systematic Review and Meta-Analysis.

BACKGROUND: The prevalence and prognosis of post-acute stage SARS-CoV-2 infection fatigue symptoms remain largely unknown. AIMS: We performed a systematic review to evaluate the prevalence of fatigue in post-recovery from SARS-CoV-2 infection. METHOD: Medline, Embase, PsycINFO, CINAHL, Web of Science, Scopus, trial registries, Cochrane Central Register of Controlled Trials, and Google Scholar were searched for studies on fatigue in samples that recovered from polymerase chain reaction (PCR) diagnosed COVID-19. English, French, and Spanish studies were included. Meta-analyses were conducted separately for each recruitment setting. RESULTS: We identified 41 studies with 9,362 patients that recovered from COVID-19. Post-COVID-19 patients self-report of fatigue was higher compared to healthy controls (risk ratio (RR) = 3.688, 95%CI [2.502, 5.436], p < .001). Over 50% of patients discharged from inpatient care reported symptoms of fatigue during the first (event rate [ER] = 0.517, 95%CI [0.278, 0.749]) and second month following recovery (ER = 0.527, 95%CI [0.337, 0.709]). Ten percent of the community patients reported fatigue in the first-month post-recovery. Patient setting moderated the association between COVID-19 recovery and fatigue symptoms (R2 = 0.11, p < .001). Female patients recovering from COVID-19 had a greater self-report of fatigue (odds ratio [OR] = 1.782, 95%CI [1.531, 2.870]). Patients recruited through social media had fatigue above 90% across multiple time points. Fatigue was highest in studies from Europe. CONCLUSION: Fatigue is a symptom associated with functional challenges which could have economic and social impacts. Developing long-term planning for fatigue management amongst patients beyond the acute stages of SARS-CoV-2 infection is essential to optimizing patient care and public health outcomes. Further studies should examine the impact of sociodemographic, pandemic-related restrictions and pre-existing conditions on fatigue.

Clinical and laboratory characteristics of clozapine-treated patients with schizophrenia referred to a national immunodeficiency clinic reveals a B-cell signature resembling common variable immunodeficiency (CVID).

AIMS: An association between antibody deficiency and clozapine use in individuals with schizophrenia has recently been reported. We hypothesised that if clozapine-associated hypogammaglobulinaemia was clinically relevant this would manifest in referral patterns. METHODS: Retrospective case note review of patients referred and assessed by Immunology Centre for Wales (ICW) between January 2005 and July 2018 with extraction of clinical and immunological features for individuals with diagnosis of schizophrenia-like illness. RESULTS: 1791 adult patients were assessed at ICW during this period; 23 patients had a psychiatric diagnosis of schizophrenia or schizoaffective disorder. Principal indications for referral were findings of low calculated globulin and immunoglobulins. Clozapine was the single most commonly prescribed antipsychotic (17/23), disproportionately increased relative to reported use in the general schizophrenia population (OR 6.48, 95% CI: 1.79 to 23.5). Clozapine therapy was noted in 6/7 (86%) of patients subsequently requiring immunoglobulin replacement therapy (IgRT). Marked reduction of class-switched memory B cells (CSMB) and plasmablasts were observed in clozapine-treated individuals relative to healthy age-matched controls. Clozapine duration is associated with CSMB decline. One patient discontinued clozapine, with gradual recovery of IgG levels without use of IgRT. CONCLUSIONS: Our findings are consistent with enrichment of clozapine-treatment within schizophrenic individuals referred for ICW assessment over the last 13 years. These individuals displayed clinical patterns closely resembling the primary immunodeficiency common variable immunodeficiency, however appears reversible on drug cessation. This has diagnostic, monitoring and treatment implications for psychiatry and immunology teams and directs prospective studies to address causality and the wider implications for this patient group.

Liaison psychiatry services in Wales.

Aims and methodRecent funding from Welsh Government for mental health has helped to develop liaison psychiatry services in Wales. Systematic data collection was undertaken to map the liaison psychiatry services in Wales in collaboration with the Royal College of Psychiatrists in Wales and Public Health Wales 1000 Lives Improvement. A questionnaire was designed and circulated to all the health boards in Wales to gather information to map liaison psychiatry services in Wales. Up-to-date information was confirmed in January 2018, via email. RESULTS: Over the past 2 years, liaison psychiatry services have been set up in six out of seven health boards in Wales. Staffing levels have increased and the remit of services has broadened.Clinical implicationsMapping has highlighted that liaison psychiatry services in Wales continue to evolve. It will be important to continue to monitor these developments and their effects. Comparison with services in England will provide a useful comparison of service provision. A particular challenge will be to establish and monitor liaison psychiatry standards in Wales.Declaration of interestNone.

Clozapine is associated with secondary antibody deficiency.

BACKGROUND: Schizophrenia affects 1% of the population. Clozapine is the only medication licensed for treatment-resistant schizophrenia and is intensively monitored to prevent harm from neutropenia. Clozapine is also associated with increased risk of pneumonia although the mechanism is poorly understood.AimsTo investigate the potential association between clozapine and antibody deficiency. METHODS: Patients taking clozapine and patients who were clozapine-naive and receiving alternative antipsychotics were recruited and completed a lifestyle, medication and infection-burden questionnaire. Serum total immunoglobulins (immunoglobulin (Ig)G, IgA, IgM) and specific IgG antibodies to haemophilus influenzae type B, tetanus and IgG, IgA and IgM to pneumococcus were measured. RESULTS: Immunoglobulins were all significantly reduced in the clozapine-treated group (n = 123) compared with the clozapine-naive group (n = 111). Odds ratios (ORs) for a reduction in clozapine:control immunoglobulin values below the fifth percentile were IgG, OR = 6.00 (95% CI 1.31-27.44); IgA, OR = 16.75 (95% CI 2.18-128.60); and IgM, OR = 3.26 (95% CI 1.75-6.08). These findings remained significant despite exclusion of other potential causes of hypogammaglobulinaemia. In addition, duration on clozapine was associated with decline in IgG. A higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year (5.3% (n = 5) versus 1% (n = 1). CONCLUSIONS: Clozapine use was associated with significantly reduced immunoglobulin levels and an increased proportion of patients using more than five antibiotic courses in a year. Antibody testing is not included in existing clozapine monitoring programmes but may represent a mechanistic explanation and modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort.Declaration of interestS.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.

The clinical effectiveness of a cognitive behavioural therapy intervention in a work setting: a 5-year retrospective analysis of outcomes.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) guidance recommends Cognitive Behavioural Therapy (CBT) as part of multidisciplinary occupational mental health interventions for people with long-term or recurrent short-term sickness absence from work (NICE, 2009). Despite this, there is a paucity of data for both randomised trials for CBT and literature that supports the transferability of CBT into occupational environments. AIMS: This service evaluation aimed to evaluate the clinical effectiveness of CBT by analysing data from a partnership scheme between a local authority and a local heath board using a routine employee population. METHODS: A clinical cohort of 81 employees referred through the partnership scheme completed CBT over a 5-year period via a CBT nurse therapist. A sample of 76 employees was included in the evaluation who completed pre-/post-measures to establish outcome. Of these, 30 were followed up at a 3-year point, completing the same measures. RESULTS: Each of the clinical measures yielded significant outcomes at 95% confidence intervals, and large effect sizes using Cohen's d both at post-test and follow-up. No significant difference was shown between post-treatment and follow-up outcomes. CBT was demonstrated to be clinically effective within an occupational mental health setting. CONCLUSIONS: In conclusion, partnership schemes with a focus on mental health between public sector agencies can have a positive outcome for the funding agency as well as individual employees.

Associated illness severity in schizophrenia and diabetes mellitus: A systematic review.

OBJECTIVE: We aimed to elucidate whether schizophrenia and type II diabetes mellitus may present with associated illness severity, in light of accumulating evidence to suggest both conditions have important shared inflammatory components with many shared inflammatory genetic factors. METHODS: We conducted a systematic review employing PRISMA criteria, searching EMBASE, Ovid MEDLINE, PsychInfo, Web of Science and Google Scholar to February 1st, 2017, for clinical studies assessing schizophrenia severity alongside dysglycaemia. A narrative synthesis was employed to discuss and compare findings between studies. RESULTS: Eleven observational studies were included in the analysis. Ten presented evidence in support of an association between schizophrenia severity and dysglycaemia. This association appeared particularly strong regarding negative symptomatology and impaired cognitive function, between which there may be some overlap. Studies examining positive symptomatology returned mixed results. CONCLUSION: Whilst study design varied amongst the included studies, the results suggest that further work examining the effect of hyperglycaemia on schizophrenia severity may be relevant, particularly longitudinal studies assessing negative symptomatology and cognitive function. To the authors' knowledge, this is the first systematic review conducted to address this question.

The Mini-Mental State Examination as a diagnostic and screening test for delirium: systematic review and meta-analysis.

OBJECTIVE: To analyse the evidence concerning the accuracy of the Mini-Mental State Examination (MMSE) as a diagnostic and screening test for the presence of delirium in adults. METHOD: Two authors searched MEDLINE, PsychINFO and EMBASE from inception till March 2014. Articles were included that investigated the diagnostic validity of the MMSE to detect delirium against standardised criteria. A diagnostic validity meta-analysis was conducted. RESULTS: Thirteen studies were included representing 2017 patients in medical settings of whom 29.4% had delirium. The meta-analysis revealed the MMSE had an overall sensitivity and specificity estimate of 84.1% and 73.0%, but this was 81.1% and 82.8% in a subgroup analysis involving robust high quality studies. Sensitivity was unchanged but specificity was 68.4% (95% CI = 50.9-83.5%) in studies using a predefined cutoff of <24 to signify a case. In high-risk samples where delirium was present in 25% of patients, then the Positive predictive value and Negative predictive value would be 50.9% (48.3-66.2%) and 93.2% (90.0-96.5%). CONCLUSION: The MMSE cannot be recommended as a case-finding confirmatory test of delirium, but may be used as an initial screen to rule out high scorers who are unlikely to have delirium with approximately 93% accuracy.

Statistical methods in randomised controlled trials for delirium.

OBJECTIVE: The analysis of clinical trials in delirium is typically complicated by treatment dropouts and by the fact that even untreated individuals may have a good prognosis. These features of delirium trials warrant special statistical attention; implications for each stage of a trial planning process are described. METHODS: Choice of outcome, patient sample, and data collection in delirium trials are discussed. Descriptions are given, together with examples, of time-to-event, imputation-based, linear and nonlinear models for the analysis of randomised controlled trials for delirium. RESULTS: Imputation allows evaluation of the plausibility of individual recovery trajectories, but some simple imputations are found to be unsuitable for delirium research. Time-to-event and nonlinear models encourage a global perspective on analysis, which is often preferable to cross-sectional end-of-trial assessments. It is suggested that nonlinear random effects models for longitudinal trajectories are particularly suitable in a delirium context. CONCLUSION: It is hoped that the methods described, and nonlinear models in particular, will play a part in convincing analyses of future delirium research.

A randomized controlled trial of quetiapine versus placebo in the treatment of delirium.

BACKGROUND: Delirium is a commonly occurring complex neuropsychiatric disorder. Evidence for its treatment based on randomized controlled trials (RCTs) is poor. AIMS: To determine the efficacy and acceptability of quetiapine in the treatment of delirium. METHOD: A double-blind, RCT was conducted. A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. Other scales used were the Brief Psychiatric Rating Scale, Mini-Mental State Examination and Clinical Global Improvement. In order to account for missing data, a nonlinear mixed-effects model was used to estimate the difference between the two groups. RESULTS: The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=.026) than the placebo group in terms of DRS-R-98 severity score. In terms of the DRS-R-98 noncognitive subscale, the quetiapine group improved 57.7% faster (S.E. 29.2%, P=.048) than the placebo group. CONCLUSIONS: Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results.

Drug treatment of delirium: past, present and future.

OBJECTIVE: The aim of this review was to summarize and critically evaluate the current literature regarding the safety and efficacy of drug therapy in delirium. We also identified recent research developments and highlighted some ongoing clinical trials to explore future directions in drug treatment and prevention of delirium. METHODS: We conducted a literature search of Medline, Embase, PsychInfo, and Cochrane Review databases, which included both prospective and retrospective clinical trials and case studies on delirium and drug therapy in adult patients up to March 2008. Abstracts from recent topical conferences were also reviewed. Ongoing delirium drug studies were identified via the WHO International Clinical Trials Registry Platform Search Portal, accessed March 12, 2008. RESULTS: The evidence base for effective drug treatment of delirium is restricted by limitations in many of the studies conducted to date. However, there has been an increase in the quantity and quality of delirium drug studies in recent years; preliminary reports and ongoing studies add to this trend. Although efficacy rates between typical and atypical antipsychotic agents are similar, the latter are associated with fewer extrapyramidal side effects. Prophylactic interventions with antipsychotic and cholinesterase inhibitors in high-risk patients provide an opportunity to improve postoperative patient care. Alternative techniques and medication opportunities could be explored in attempts to minimize drug induced delirium potential. CONCLUSIONS: Appropriate drug therapy should be considered part of systematic approaches to delirium treatment and prevention. There is a need for well-designed randomized, double-blind placebo-controlled trials investigating the drug management of various aspects of delirium, including delineating treatment by delirium subtype, dose ranging studies, and optimal duration of therapy.