Early neutrophil trajectory following clozapine may predict clozapine response - Results from an observational study using electronic health records.

BACKGROUND: Clozapine has unique effectiveness in treatment-resistant schizophrenia and is known to cause immunological side-effects. A transient spike in neutrophils commonly occurs in the first weeks of clozapine therapy. There is contradictory evidence in the literature as to whether neutrophil changes with clozapine are linked to treatment response. AIMS: The current study aims to further examine the neutrophil changes in response to clozapine and explore any association between neutrophil trajectory and treatment response. METHODS: A retrospective cohort study of patients undergoing their first treatment with clozapine and continuing for at least 2 years identified 425 patients (69% male/31% female). Neutrophil counts at baseline, 3 weeks and 1 month were obtained predominantly by linkage with data from the clozapine monitoring service. Clinical Global Impression- Severity (CGI-S) was rated from case notes at the time of clozapine initiation and at 2 years. Latent class growth analysis (LCGA) was performed to define distinct trajectories of neutrophil changes during the first month of treatment. Logistic regression was then conducted to investigate for association between the trajectory of neutrophil count changes in month 1 and clinical response at 2 years as well as between baseline neutrophil count and response. RESULTS: Of the original cohort, 397 (93%) patients had useable neutrophil data during the first 6 weeks of clozapine treatment. LCGA revealed significant differences in neutrophil trajectories with a three-class model being the most parsimonious. The classes had similar trajectory profiles but differed primarily on overall neutrophil count: with low, high-normal and high neutrophil classes, comprising 52%, 40% and 8% of the sample respectively. Membership of the high-normal group was associated with significantly increased odds of a positive response to clozapine, as compared to the low neutrophil group [Odds ratio (OR) = 2.10, p-value = 0.002; 95% confidence interval (95% CI) = 1.31-3.36]. Baseline neutrophil count was a predictor of response to clozapine at 2 years, with counts of ≥5 × 109/l significantly associated with positive response (OR = 1.60, p-value = 0.03; 95% CI = 1.03-2.49). CONCLUSIONS: Our data are consistent with the hypothesis that patients with low-level inflammation, reflected in a high-normal neutrophil count, are more likely to respond to clozapine, raising the possibility that clozapine exerts its superior efficacy via immune mechanisms.

Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension.

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus.

Pulmonary arterial hypertension (PAH) is estimated to affect between 10 and 50 people per million worldwide. The lack of cure and devastating nature of the disease means that treatment is crucial to arrest rapid clinical worsening. Current therapies are limited by their focus on inhibiting residual vasoconstriction rather than targeting key regulators of the cellular pathology. Potential disease-modifying therapies may come from research directed towards causal pathways involved in the cellular and molecular mechanisms of disease. It is widely acknowledged that targeting reduced expression of the critical bone morphogenetic protein type-2 receptor and its associated signalling pathways is a compelling therapeutic avenue to explore. In this review, we highlight the advances that have been made in understanding this pathway and the therapeutics that are being tested in clinical trials and the clinic to treat PAH.

Prevalence of treatment resistance and clozapine use in early intervention services.

BACKGROUND: Treatment resistance causes significant burden in psychosis. Clozapine is the only evidence-based pharmacologic intervention available for people with treatment-resistant schizophrenia; current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics. AIMS: This paper aims to explore the prevalence of treatment resistance and pathways to commencement of clozapine in UK early intervention in psychosis (EIP) services. METHOD: Data were taken from the National Evaluation of the Development and Impact of Early Intervention Services study (N = 1027) and included demographics, medication history and psychosis symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, 6 months and 12 months. Prescribing patterns and pathways to clozapine were examined. We adopted a strict criterion for treatment resistance, defined as persistent elevated positive symptoms (a PANSS positive score ≥16, equating to at least two items of at least moderate severity), across three time points. RESULTS: A total of 143 (18.1%) participants met the definition of treatment resistance of having continuous positive symptoms over 12 months, despite treatment in EIP services. Sixty-one (7.7%) participants were treatment resistant and eligible for clozapine, having had two trials of standard antipsychotics; however, only 25 (2.4%) were prescribed clozapine over the 12-month study period. Treatment-resistant participants were more likely to be prescribed additional antipsychotic medication and polypharmacy, instead of clozapine. CONCLUSIONS: Prevalent treatment resistance was observed in UK EIP services, but prescription of polypharmacy was much more common than clozapine. Significant delays in the commencement of clozapine may reflect a missed opportunity to promote recovery in this critical period.

Acute psychosis in glycogen storage disease: a rare but severe complication.

Glycogen storage disease type 1 (GSD-1) is a group of inherited metabolic disorders characterised by the inability to use intracellular glucose stores. It is associated with a high risk of hypoglycaemia, as well as long-term complications including growth retardation, hepatocellular adenomas, renal disease, hypertriglyceridaemia and hyperuricaemia. Treatment involves slow absorption carbohydrates, for example, cornstarch. We present a case of acute psychosis in a patient with GSD-1a. This was initially attributed to his opiate use. Later in his management an MRI scan of his head was performed which revealed regions of brain atrophy following significant hypoglycaemic insult, thus identifying an organic cause of his psychosis. This case presents a rare complication of glycogen storage disease: organic psychosis attributable to cortical atrophy from profound hypoglycaemic insult. It emphasises the importance of investigating organic causes of psychiatric symptoms.

Clozapine discontinuation in early schizophrenia: a retrospective case note review of patients under an early intervention service.

AIM: Research in patients with treatment-resistant schizophrenia has demonstrated that clozapine discontinuation is associated with poor outcomes. There is, however, a paucity of research investigating the impact of clozapine discontinuation specifically in younger patients with more recent onset schizophrenia. A case note review was therefore conducted to ascertain medium-term prognoses in patients with treatment-resistant schizophrenia under an early intervention service (EIS) following clozapine discontinuation. METHODS: The case notes of 25 patients under the care of Birmingham EIS who discontinued clozapine were examined retrospectively. Reasons for discontinuation were recorded. Clinical outcomes including total duration of inpatient or home treatment admission, antipsychotic dose, number of alternative antipsychotics prescribed and adverse events were recorded for both the year before and the year after stopping clozapine. Statistical comparisons of pre- and post-discontinuation clinical outcomes determined whether discontinuation had negative effects. RESULTS: There was no significant difference between the pre- and post-discontinuation clinical status following clozapine discontinuation. More than half (56%) of patients remained stable after stopping clozapine. Mean inpatient or home treatment stay rose from 29.7 to 62.6 days (p = 0.155), total antipsychotic dose from 50.1% of British National Formulary (BNF) limits to 60.5% (p = 0.627), number of alternative antipsychotics prescribed from 1.28 to 1.80 (p = 0.186), number of hospital/home treatment episodes from 0.20 to 0.44 (p = 0.083) and number of adverse events from 0 to 0.20 (p = 0.059). Non-compliance was the main reason for discontinuation (44%, n = 11). CONCLUSIONS: This is the first clozapine discontinuation study specifically considering EIS patients. Discontinuation did not lead to significant effects on 1 year outcomes, though the study is underpowered. These findings may be used to inform future prospective cohort discontinuation studies.

Rates of criminal victimization in an early intervention for psychosis service - a cross sectional survey.

BACKGROUND: There is a growing body of research looking into the high rates of victimization amongst people with severe mental illness. Studies to date have tended to look at victimization rates in people with chronic mental illness over a wide age range. However, national crime surveys indicate that younger people are more likely to be the victim of crime than older people. There is also evidence that people from ethnic minorities are more likely to experience and less likely to report criminal victimization. This study therefore aimed to look at victimization rates specifically in young people with first episode psychosis (FEP) in Birmingham, one of the most youthful and ethnically diverse cities in the UK. METHODS: Patients with FEP under the South Birmingham Early Intervention Service were asked to complete a modified version of the Crime Survey for England and Wales (CSEW). Data was compared to control-group data from the CSEW 2014. RESULTS: Patients with FEP were significantly more likely to be victims of crime, in particular violent crime, than their age-matched counterparts. The overall victimization rate was 39%. Black and Minority Ethnic (BME) groups were more likely to be victims of personal and violent crime than the white FEP population. Victimization rates were broadly in keeping with other UK and international studies. CONCLUSIONS: Young people with FEP, particularly those from BME backgrounds, are at significantly greater risk of victimhood than the general population of the West Midlands.

Staff attitudes towards particular client difficulties in assertive outreach teams.

OBJECTIVE: Over recent years in England there has been widespread development of assertive outreach teams supporting patients with severe mental illness living in the community. Assertive outreach staff members are exposed to a variety of new stressors and risks. This study investigated the emotional impact on keyworkers of working with assertive outreach patients. This was considered in terms of the attitudes keyworkers hold towards patients with particular types of difficulty. The study also measured individual keyworker stress. METHODS: Keyworkers from three teams in Birmingham were surveyed regarding their attitudes towards individual patients. Questionnaires measuring attitudes and patient difficulties were derived for the purpose of the study. Strengths of attitudes were correlated against different patient difficulties. Keyworker stress was measured using the General Health Questionnaire, GHQ12. RESULTS: Certain patient difficulties, in particular poor engagement, psychotic symptoms and aggression were associated with feelings of failure in keyworkers whilst drug use, particularly crack cocaine use, was associated with fear of visiting patients at home. Some 41% of keyworkers met 'caseness' criteria on the GHQ12. Negative attitudes appeared to be independent of GHQ scores. CONCLUSIONS: Keyworkers expressed a number of positive and negative attitudes in relation to patient difficulties. Negative attitudes did not appear to be simply a feature of keyworker stress, however it is acknowledged that the sample size was small. Keyworkers' responses suggested a sense of personal failure when their patients were unwell or poorly engaged, despite patients being selected for assertive outreach on the basis of such difficulties. Recognition of negative attitudes may help in the improvement of training and supervision of staff members.

Quantitative risk assessment of rabies entering Great Britain from North America via cats and dogs.

Great Britain has been rabies-free since 1922, which is often considered to be in part due to the strict laws requiring that imported cats and dogs be vaccinated and quarantined for 6 months immediately on entry into the country. Except for two isolated incidents, this quarantine policy has contributed to ensuring that Great Britain has remained free of rabies. In 2000, amendments to the UK quarantine laws were made and the Pet Travel Scheme (PETS) was launched for companion animals traveling from European Union countries and rabies-free islands. Since its introduction, it has been proposed that other countries including North America should be included within the UK scheme. A quantitative risk assessment was developed to assist in the policy decision to amend the long-standing quarantine laws for dogs and cats from North America. It was determined that the risk of rabies entry is very low and is dependent on the level of compliance (i.e., legally conforming to all of the required regulations) with PETS and the number of pets imported. Assuming 100% compliance with PETS and the current level of importation of cats and dogs from North America, the annual probability of importing rabies is lower for animals traveling via PETS (7.22 x 10(-6), 95th percentile) than quarantine (1.01 x 10(-5), 95th percentile). These results, and other scientific evidence, directly informed the decision to expand the PETS scheme to North America as of December 2002.