Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

[Referral of a stabilized patient with psychotic disorder to the general practitioner: a pilot study]. / Verwijzing van gestabiliseerde patiënt met psychotische stoornis naar huisarts: kan dat? Een vooronderzoek.

BACKGROUND: In various countries, general practitioners (GPs) play an important role after treatment for non-affective psychotic disorder (NAPD) in mental health care. It is unclear how these patients fare. AIM: To compare the clinical course of patients largely recovered from NAPD and referred to the GP with the course of patients who remain in treatment at mental healthcare. METHOD: In a retrospective cohort study, 20 patients referred to GPs by mental healthcare (GP cohort) were compared to 20 patients who remained in treatment at mental healthcare (MH cohort), matched by age and gender. The clinical course was evaluated with the GPs and the mental healthcare practitioner, respectively. In addition, medication adherence and reasons for referral to the GP and mental healthcare were registered. RESULTS: In the GP cohort more patients (70%) deteriorated than in the MH cohort (5%) (p <0.001). In the MH cohort more patients showed therapeutic compliance (90%) than in the GP cohort (67%) (p = 0.078). After about four years, 65% of the patients in the GP cohort were back in treatment at mental healthcare. Among the 13 patients who were referred to the GP while functioning stably, more patients (54%) deteriorated than their matched counterparts in the MH cohort (8%) (p = 0.034). CONCLUSION: The results confirm that caution is needed in referring patients recovered from non-affective psychotic disorder to the GP.

[COVID-19 and severe mental illness, especially in clozapine use]. / COVID-19 en ernstige psychiatrische aandoeningen, in het bijzonder bij clozapinegebruik.

BACKGROUND: The Clozapine Plus Working Group is frequently consulted for advice on measures in case of infection with SARSCoV-2 and on vaccination against COVID-19 in patients receiving clozapine.

AIM: Inform about risks of infection with SARS-CoV-2 in patients with severe mental illness (SMI), patients with schizophrenia spectrum disorders (SSD), and patients treated with clozapine. Advise on monitoring of clozapine plasma levels and white blood cell count and differential in COVID-19 and after vaccination, as well as measures to be taken.

METHOD: Literature research and case studies.

RESULTS: SMI patients and in particular SSD patients have an increased risk of infection with SARS-CoV-2 with more hospitalizations and higher mortality than non-psychiatric patients. Patients using clozapine may be at greater risk of infection. SARS-CoV-2 infection may cause a dangerous increase of clozapine plasma levels and generally mild and short-term granulocytopenia and lymphocytopenia, which are usually not a result of clozapine treatment.

CONCLUSION: In case of COVID-19 extra alertness is required in patients with SMI and especially SSD. In clozapine users, in case of COVID-19, reduction in dose by half to three quarters of the original dose is recommended. When patients develop granulocytopenia, SARS-CoV-2 should be considered as the cause and not immediately clozapine. SMI patients and clozapine users in particular belong to a high risk group with a medical indication for early vaccination.

[Clozapine treatment and COVID-19: continue despite leukocytopenia and increase of clozapine serum levels]. / Clozapinebehandeling en COVID-19: doorgaan ondanks leukocytopenie en spiegelstijging.

Clozapine is an antipsychotic with clozapine-induced agranulocytosis (CIA) as a rare, but potentially life-threatening side-effect, for which the white blood cell count and absolute neutrophil count are routinely monitored. Observed leukopenia may lead to more frequent monitoring, or even acute discontinuation of clozapine treatment. COVID-19 may cause deviating blood parameters such as leukopenia, and more exceptionally even granulocytopenia, just as clozapine does. In case of a SARS-CoV-2 infection and leukopenia, it is important to differentiate whether the reduced white blood cell count is caused by clozapine - in which case it needs to be stopped immediately - or as a consequence of infection with the coronavirus. In case of a mild leukopenia, based on a lymphopenia, clozapine can be safely continued with more frequent blood monitoring. Additionally, the dosage of clozapine should be reduced by half, due to the risk of a sudden increase of clozapine serum levels.

[Validation of the Dutch Glasgow Anti- psychotic Side-Effect Scale for Clozapine]. / Glasgow Antipsychotica Bijwerkingen Schaal voor Clozapine; validatie van de Nederlandstalige versie.

BACKGROUND: To monitor the unique side effect pattern of clozapine, the Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C) was developed in English and validated. This questionnaire was previously translated to Dutch, and revised, but not yet validated. AIM: The current study concerns the validation of the second revision of the GASS-C-NL-R2 for the Dutch language. METHOD: Two Spearman correlation tests were conducted to compare GASS-C-NL-R2 with the Dutch version of the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) at two time p´oints. There was one week between these two time points. The test-retest reliability was determined using a Spearman correlation test and Cronbach's alpha on the GASS-C-NL-R2 between the two time points. In addition, a factor analysis was performed. RESULTS: Spearman's correlation coefficient between the GASS-C-NL-R2 and the LUNSERS was 0.830 (p < 0.001, n = 72) at the first time point and 0.684 (p < 0.001, n = 50) at the second time point. GASS-C-NL-R2 also had a strong test-retest reliability: Spearman's correlation coefficient was 0.680 (p < 0.001; n = 46), and Cronbach's alpha was 0.847, n = 78. Factor analysis showed that all questions were relevant. CONCLUSION: The current study shows that GASS-C-NL-R2 is a valid and reliable questionnaire to monitor side effects related to clozapine with a relatively high prevalence. Future studies should focus on the practical utility of GASS-C-NL-R2 with a larger sample size.

[Recognizing borderline intellectual functioning or mild intellectual disability in newly registered patients in a general psychiatric outpatient clinic]. / Onderkennen van zwakbegaafdheid of een lichte verstandelijke beperking bij aangemelde patiënten op een algemene psychiatrische polikliniek.

BACKGROUND: It is unclear whether borderline intellectual functioning (bif) and/or a mild intellectual disability (mid) in patients receiving treatment in mental health care are being recognized by care providers.
AIM: Exploratory study to register under-diagnosis of bif/mid in an outpatient clinic.
METHOD: The number of patients diagnosed with bif/mid according to the electronic patient file (epd) was determined. From 11 August to 11 December 2015, all newly registered patients for outpatient treatment with an mbo-2 or lower educational level were screened for the possible presence of bif/mid applying the screener for intelligence and mild intellectual disability (scil). For all patients, their mental health care practitioner was asked if they suspected bif/mid. These percentages were compared. The sensitivity and specificity and the positive and negative predictive value (ppv and npv) of the opinion of the mental health care practitioners were determined.
RESULTS: In the epd 2,8% of patients were diagnosed with bif, and 0,8% with mid. The percentage of suspected bif/mid of newly registered patients was 17,5%. The sensitivity of the assessors' opinion was 41%, the npv was 57%.
CONCLUSION: In newly registered patients at an outpatient clinic bif and mid are important but frequently missed co-morbidities.

Delegating Clozapine Monitoring to Advanced Nurse Practitioners: An Exploratory, Randomized Study to Assess the Effect on Prescription and Its Safety.

To test whether: (1) psychiatrists will prescribe clozapine more often if they can delegate the monitoring tasks to an advanced nurse practitioner (ANP), (2) clozapine monitoring by an ANP is at least as safe as monitoring by a psychiatrist. Patients from 23 Dutch outpatient teams were assessed for an indication for clozapine. ANPs affiliated to these teams were randomized to Condition A: clozapine monitoring by an ANP, or Condition B: monitoring by the psychiatrist. The safety of monitoring was evaluated by determining whether the weekly neutrophil measurements were performed. Staff and patients were blinded regarding the first hypothesis. Of the 173 patients with an indication for clozapine at baseline, only seven in Condition A and four in Condition B were prescribed clozapine (Odds Ratio = 2.24, 95% CI 0.61-8.21; p = 0.225). These low figures affected the power of this study. When we considered all patients who started with clozapine over the 15-month period (N = 49), the Odds Ratio was 1.90 (95% CI 0.93-3.87; p = 0.078). With regard to the safety of the monitoring of the latter group of patients, 71.2% of the required neutrophil measurements were performed in condition A and 67.3% in condition B (OR = 0.98; CI = 0.16-3.04; p = 0.98). Identifying patients with an indication for clozapine does not automatically lead to improved prescription rates, even when an ANP is available for the monitoring. Clozapine-monitoring performed by an ANP seemed as safe as that by a psychiatrist.

Evaluation of the performance of a point-of-care method for total and differential white blood cell count in clozapine users.

INTRODUCTION: We evaluated the performance of the HemoCue WBC DIFF, a point-of-care device for total and differential white cell count, primarily to test its suitability for the mandatory white blood cell monitoring in clozapine use. METHOD: Leukocyte count and 5-part differentiation was performed by the point-of-care device and by routine laboratory method in venous EDTA-blood samples from 20 clozapine users, 20 neutropenic patients, and 20 healthy volunteers. From the volunteers, also a capillary sample was drawn. Intra-assay reproducibility and drop-to-drop variation were tested. RESULTS: The correlation between both methods in venous samples was r > 0.95 for leukocyte, neutrophil, and lymphocyte counts. The correlation between point-of-care (capillary sample) and routine (venous sample) methods for these cells was 0.772; 0.817 and 0.798, respectively. Only for leukocyte and neutrophil counts, the intra-assay reproducibility was sufficient. CONCLUSION: The point-of-care device can be used to screen for leukocyte and neutrophil counts. Because of the relatively high measurement uncertainty and poor correlation with venous samples, we recommend to repeat the measurement with a venous sample if cell counts are in the lower reference range. In case of clozapine therapy, neutropenia can probably be excluded if high neutrophil counts are found and patients can continue their therapy.

[First generation versus second generation antipsychotics: little benefit in the real world]. / Nieuwe versus oude antipsychotica: weinig voordelen in echte wereld.

In the last five years seven independently financed studies comparing first and second generation antipsychotics (FGAS and SGAS) have been published. Most of these studies were conducted among patients attending regular psychiatric practices. The results show that very few or no advantages are to be gained from using SGAS rather than FGAS. In general, the clinical effectiveness is not increased, but the side-effects are different. The effectiveness studies in fact definitely justify the selection of FGAS (particularly those of low and medium potency) if a change in medication is indicated.

How can antipsychotics cause Diabetes Mellitus? Insights based on receptor-binding profiles, humoral factors and transporter proteins.

The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle.

[Granulocytopenia while using clozapine: continuing or stopping treatment]. / Granulocytopenie bij clozapine: doorgaan of stoppen met behandeling.

BACKGROUND: This article describes four patients using clozapine, with neutropenia. Clozapine-induced neutropenia can be one of three types: pseudo, benign or malignant. The malignant type can give cause for serious concern; in that case treatment with clozapine must be stopped. Pseudo-neutropenia and benign neutropenia, however, occur frequently. In these cases it is probably unnecessary to stop clozapine medication, particularly if clozapine is clearly indicated.

[Dose reduction of conventional antipsychotics: does it reduce tardive dyskinesia?]. / Dosisreductie van klassieke antipsychotica: gunstig voor tardieve dyskinesie?

The first step in the treatment of tardive dyskinesia is to reduce the dose of antipsychotics. The view sometimes expressed in general practice is that, initially, dose reduction exacerbates tardive dyskinesia, which is an effect that can be explained on theoretical grounds. However, it is apparent from published scientific research that dose reduction of conventional antipsychotics tends to improve tardive dyskinesia rather than exacerbate it.