Feasibility and Effect of Increasing Clozapine Plasma Levels in Long-Stay Patients With Treatment-Resistant Schizophrenia.

BACKGROUND: It is unknown whether increasing the clozapine plasma level to 400, 750, or even 1000 ng/mL is a feasible and effective strategy in patients with treatment-resistant schizophrenia (TRS). We investigated this in long-stay patients with TRS. METHODS: In long-stay TRS patients, doses of clozapine were increased gradually to reach target plasma levels of 400, 750, or 1000 ng/mL, depending on the clinical response and tolerability. After an effective or tolerated level was reached, positive and negative syndrome scale scores were evaluated after 3 months and 1 year. RESULTS: Twenty-eight patients were included. Overall, 54% of the patients, and especially patients 60 years and older, could not achieve one of the clozapine target levels because of adverse effects. Three physically vulnerable patients died, probably not directly related to clozapine use. Although only 21% of patients achieved a more than 20% reduction in total symptoms at the 1-year follow-up, the mean severity of positive symptoms decreased from 18.18 to 15.10 ( P < 0.01). The largest decrease in positive symptoms was seen in TRS patients who achieved a plasma level of 750 ng/mL of clozapine. CONCLUSIONS: Most TRS patients older than 60 years could not tolerate high clozapine levels and so this should not be attempted in older or otherwise physically vulnerable patients. Increasing clozapine levels to approximately 750 ng/mL in middle-aged patients with longstanding TRS may modestly reduce the severity of positive symptoms and improve the response rate.

Clozapine and COVID-19 Vaccination: Effects on blood levels and leukocytes. An observational cohort study.

OBJECTIVE: To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters. METHODS: We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 µg/L increase compared to baseline) and clozapine alert levels (>1000 µg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID-19 vaccine. RESULTS: This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline. CONCLUSION: In general, as regards WBC counts COVID-19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C-reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination.

COVID-19: Risks, Complications, and Monitoring in Patients on Clozapine.

The Dutch Clozapine Collaboration Group is frequently asked for advice about the management of clozapine-treated patients when infected with or vaccinated against SARS-CoV-2. We provide state of the art information about the risks of SARS-CoV-2 infection for patients on clozapine and we give advice on measures to be taken, especially in regard to the monitoring of clozapine plasma levels, WBC count and differentiation during COVID-19 and after vaccination. We present an overview of relevant editorials, observational studies, and case studies, in which COVID-19 was reported in patients on clozapine. Patients using clozapine may have a higher risk of infection than patients with schizophrenia spectrum disorders (SSD) using other antipsychotics. SARS-CoV-2 infection can result in a dangerous increase of clozapine plasma levels, and granulocytopenia and lymphocytopenia (generally mild and short-term) may also occur, usually not as a result of clozapine treatment. Clozapine intoxication, pneumonia and delirium are the main complications of COVID-19 in patients on clozapine. In order to prevent clozapine intoxication, reduction of the original dose by half is generally recommended in clozapine users who contract COVID-19. When a cytokine storm is suspected in an advanced stage of COVID-19, reduction by three quarters seems more appropriate. If COVID-19 patients on clozapine develop granulocytopenia, SARS-CoV-2, rather than clozapine, should be considered as the cause. Schizophrenia patients in general and clozapine users in particular belong to a high-risk group that warrants early vaccination on a medical indication.

The incidence and economic impact of aggression in closed long-stay psychiatric wards.

OBJECTIVE: Aggressive behaviour is highly prevalent in long-term psychiatric inpatient care. We aimed to estimate the overall incidence of aggression, the time staff took to handle aggression incidents, and the weighted average financial costs thereof. METHODS: A random sampling procedure was conducted at long-term psychiatric inpatient care facilities. Nurses were asked to recall all incidents (i.e., verbal, physical towards objects, self, or others) of their shift. For the time spent on each type of incident, staff were monitored in real-time. Estimated costs were calculated by the time spent multiplied by hourly wages in addition to material-related costs. RESULTS: Incidence rates were 90 incidents per patient year. The average time spent per incident was 125 min but differed for each type of incident. Almost 80% of this time was consumed by nursing staff. The average cost per aggression incident was €78; extrapolated per patient year, the total costs were approximately €7000. CONCLUSIONS: The current study found a high rate of aggression incidents in closed long-stay psychiatric wards. Reports of aggression on these types of wards are scarce. Nevertheless, aggression seems to have a severe impact on invested time and related costs, which suggests a need for aggression-prevention and de-escalating programs.Key pointsAggression incidents are highly prevalent and are accompanied by high costs.The effect of aggression incidents on the workload for staff members is high, especially for nursing staff.Studies across countries on the incidence and the costs of aggression among psychiatric inpatients are needed to help model the effects of (new) strategies for aggression reduction.

Diagnostic value of a simplified screening test for metabolic syndrome in a Dutch patient cohort with schizophrenia spectrum disorders.

OBJECTIVE:: The aim of this study was to establish the specificity and sensitivity of a simplified screening test based on diastolic blood pressure and waist circumference for predicting metabolic syndrome. METHOD:: Demographic, anthropometric (waist circumference and systolic and diastolic blood pressure) and laboratory (triglyceride, high-density lipoprotein and fasting glucose) data were collected from a large cohort of Dutch patients with a schizophrenia spectrum disorder in order to determine whether patients fulfilled the Western criteria of the International Diabetes Federation (IDF) for metabolic syndrome. The sensitivity, specificity, likelihood ratio of a positive or negative test outcome and positive and negative predictive values of the simplified test (only waist circumference and diastolic blood pressure) were calculated. RESULTS:: Of 252 recruited patients, 55% met the IDF criteria for metabolic syndrome. The sensitivity and the specificity of the simplified test were 65% and 85%, respectively. The likelihood ratios of positive and negative test outcomes were 4.35 and 0.41, respectively, and the positive and negative predictive values were 87% and 67%, respectively. CONCLUSION:: This simplified screening test did not have diagnostic validity for metabolic syndrome in a Dutch cohort of patients with schizophrenia spectrum disorder.

Low levels of vitamin D poorly responsive to daylight exposure in patients with therapy-resistant schizophrenia.

BACKGROUND: Low vitamin D levels are associated with schizophrenia, but the possible association between vitamin D levels and illness severity or duration of exposure to daylight has barely been investigated. AIMS: To compare vitamin D levels in therapy-refractory severely ill schizophrenia patients and members of staff. To investigate the influence of daylight exposure on vitamin D levels in patients. METHODS: Vitamin D was measured in patients with therapy-resistant schizophrenia in April, after the winter, and in patients and staff members in June, after an exceptionally sunny spring. Vitamin D levels in April and June were compared in patients, and levels in June were compared in patients and staff. The influence of daylight was taken into account by comparing the time patients spent outdoors during the day with the recommended minimum time for adequate vitamin D synthesis, and by comparing time spent outdoors in patients and staff. RESULTS: Patients had high rates of vitamin D deficiency (79-90%) and lower levels of vitamin D than staff members (p < 0.001), independent of skin pigmentation. In patients, vitamin D levels did not normalize, despite the considerably longer than recommended exposure of the skin to daylight (p < 0.001) and the longer exposure in patients than in staff members (p = 0.003). CONCLUSION: The vitamin D deficiency of therapy-resistant schizophrenia patients is pronounced and cannot be explained by differences in skin pigmentation or by an inactive, indoor lifestyle on the ward. Even theoretically sufficient exposure of the patients to daylight did not ameliorate the low vitamin D levels. CLINICAL IMPLICATIONS: While vitamin D deficiency probably plays a role in somatic health problems, it may also play a role in schizophrenia. Interestingly, exposure to daylight during an unusually sunny spring was not sufficient to correct the vitamin D deficiency seen in the patients. This emphasizes the need to measure and correct vitamin D levels in these patients.

Cognitive Effects of Reducing First-Generation Antipsychotic Dose Compared to Switching to Ziprasidone in Long-Stay Patients with Schizophrenia.

Background: Cognitive impairment is a core symptom of schizophrenia and is associated with functional outcomes. Improving cognitive function is an important treatment goal. Studies have reported beneficial cognitive effects of the second-generation antipsychotic (SGA) ziprasidone. Reducing the dose of first-generation antipsychotics (FGA) might also improve cognitive function. This study compared the cognitive effects in long-stay patients who were randomized to groups who underwent FGA dose reduction or switched to ziprasidone. Methods: High-dose FGA was reduced to an equivalent of 5 mg of haloperidol in 10 patients (FGA-DR-condition), and 13 patients switched to ziprasidone 80 mg b.i.d. (ZIPRA condition). Five domains of cognitive function were assessed before dose reduction or switching (T0) and after 1 year (T1). This study was approved by the ethics committee of the Open Ankh (CCMO number 338) and registered at the Netherlands Trial Register (code 5864). Results: Non-significant deterioration was seen in all cognitive domains studied in the FGA-DR condition, whereas there was a non-significant improvement in all cognitive domains in the ZIPRA condition. The most robust difference between conditions, in favor of ziprasidone, was in executive function. Conclusions: In patients with severe chronic schizophrenia, ziprasidone had a non-significant and very modest beneficial effect on cognitive function compared with FGA dose reduction. Larger trials are needed to further investigate this effect.

Risk Factors for Psychotic Relapse After Dose Reduction or Discontinuation of Antipsychotics in Patients With Chronic Schizophrenia. A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND HYPOTHESIS: Although maintenance treatment with antipsychotics protects against psychotic relapse, high doses may hamper recovery. Therefore, dose reduction or discontinuation may be considered in patients with chronic schizophrenia. Here, we identified risk factors for psychotic relapse when doses are reduced. STUDY DESIGN: We systematically searched MEDLINE, EMBASE, and PsycINFO from January 1950 through January 2021 and reviewed randomized controlled trials (RCTs) that reported relapse rates after antipsychotic dose reduction or discontinuation in patients with chronic schizophrenia. We calculated relative risks (RRs) with 95% confidence intervals (CIs) per person-year and sought to identify potential risk factors for relapse. The study is registered with PROSPERO (CRD42017058296). STUDY RESULTS: Forty-seven RCTs (54 patient cohorts, 1746 person-years) were included. The RR for psychotic relapse with dose reduction/discontinuation versus maintenance treatment was 2.3 per person-year (95% CI: 1.9 to 2.8). The RR was higher with antipsychotic discontinuation, dose reduction to less than 3-5 mg haloperidol equivalent (HE), or relatively rapid dose reduction (<10 weeks). The RR was lower with long-acting injectable agents versus oral antipsychotic dose reduction. Other factors that increased the risk of psychotic relapse were younger age and short follow-up time. CONCLUSIONS: Clinicians should take several risk factors for psychotic relapse into account when considering dose reduction in patients with chronic schizophrenia. Studies of a relatively fast reduction in antipsychotic dose support a minimum dose of 3-5 mg HE. However, if the dose is tapered more gradually, relapses related to medication withdrawal might be avoided, possibly enabling lower-end doses to be achieved.

Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring: Can the regulations be relaxed?

After the introduction of clozapine eight Finnish patients died after developing agranulocytosis. Clozapine was withdrawn from the market and only reintroduced with strict mandatory white blood cell monitoring as long as treatment lasts and thresholds at which clozapine must be discontinued definitively. The fear of agranulocytosis and the need for intensive blood monitoring is the single most important barrier for prescribers and patients alike and leads to underprescription of the only effective and approved medication for treatment-resistant schizophrenia. We summarize evidence that the risk of agranulocytosis is smaller than perceived at the time of reintroduction, is concentrated in the first 18 weeks of treatment, is not greater than with other antipsychotics thereafter and that frequent blood monitoring has not demonstrably decreased the rate of agranulocytosis. Therefore we propose 1) mandatory monitoring of the absolute neutrophil count (ANC) exclusively during the first 18 weeks of clozapine treatment, 2) that thereafter the prescriber and the well-informed patient decide together about further monitoring frequency, 3) that clozapine treatment must be stopped if the ANC falls below 1.0 × 109/L. Continuation of clozapine or a rechallenge are possible if prescriber and patient determine that the benefits outweigh the risks. 4) National registries which control the haematologic monitoring are unnecessary and do not help to reduce clozapine-induced agranulocytosis. They should at least be restricted to the first 18 weeks of clozapine use.

Effects of multivitamin, mineral and n-3 polyunsaturated fatty acid supplementation on aggression among long-stay psychiatric in-patients: randomised clinical trial.

BACKGROUND: Aggression and violent incidents are a major concern in psychiatric in-patient care. Nutritional supplementation has been found to reduce aggressive incidents and rule violations in forensic populations and children with behavioural problems. AIMS: To assess whether multivitamin, mineral and n-3 polyunsaturated fatty acid supplementation would reduce the number of aggressive incidents among long-stay psychiatric in-patients. METHOD: The trial was a pragmatic, multicentre, randomised, double-blind placebo-controlled study. Data were collected from 25 July 2016 to 29 October 2019, at eight local sites for mental healthcare in The Netherlands and Belgium. Participants were randomised (1:1) to receive 6-month treatment with either three supplements containing multivitamins, minerals and n-3 polyunsaturated fatty acid, or placebo. The primary outcome was the number of aggressive incidents, determined by the Staff Observation Aggression Scale - Revised (SOAS-R). Secondary outcomes were patient quality of life, affective symptoms and adverse events. RESULTS: In total, 176 participants were randomised (supplements, n = 87; placebo, n = 89). Participants were on average 49.3 years old (s.d. 14.5) and 64.2% were male. Most patients had a psychotic disorder (60.8%). The primary outcome of SOAS-R incidents was similar in supplement (1.03 incidents per month, 95% CI 0.74-1.37) and placebo groups (0.90 incidents per month, 95% CI 0.65-1.19), with a rate ratio of 1.08 (95% CI 0.67-1.74, P = 0.75). Differential effects were not found in sensitivity analyses on the SOAS-R or on secondary outcomes. CONCLUSIONS: Six months of nutritional supplementation did not reduce aggressive incidents among long-stay psychiatric in-patients.

HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

Differences between physicians' and nurse practitioners' viewpoints on reasons for clozapine underprescription.

INTRODUCTION: Clozapine (CLZ) is the only proven effective therapy for treatment-resistant schizophrenia, but it is underutilized across the globe. Previous findings suggest a lack of experience with CLZ prescription and concerns about CLZ's pharmacological characteristics are the prime reasons for CLZ underutilization. To our knowledge, it is currently unknown whether the reasons for underutilization and suggested solutions differ between physicians and nurse practitioners. Such differences are important as nurse practitioners are becoming increasingly involved in prescribing CLZ. METHODS: To examine to what degree physicians and nurse practitioners differ with regard to their take on reasons for CLZ underutilization and suggested solutions, an online questionnaire was distributed to physicians and nurse practitioners. The primary outcome was to compare the patient-related and prescriber-related reasons for CLZ underprescription between physicians and nurse practitioners, while secondary outcome measures included the potential solutions to prevent this underprescription. RESULTS: Physicians (N = 112) and nurse practitioners (N = 41) agreed that the two most common reasons for underprescription (patient-related and prescriber-related) were refusal to undergo regular blood tests and side-effect concerns. They also agreed that the third most common prescriber-related reason was medical complications. Physicians rated patients' unwillingness to switch medication as the third most common reason for CLZ underprescription, whereas nurse practitioners rated refusal to undergo baseline bloodtests as the third most common reason. The solutions to reduce underprescription largely corresponded between both groups. CONCLUSIONS: We conclude that slight differences exist between physicians' and nurse practitioners' viewpoints on patient-related and prescriber-related reasons for CLZ underprescription. Future research projects should involve patients to elucidate whether the patient-related factors put forward by prescribers align with the patients' opinions.

Dose reduction of high-dose first-generation antipsychotics or switch to ziprasidone in long-stay patients with schizophrenia: A 1-year double-blind randomized clinical trial.

Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms and side effects. We investigated in a randomized double-blind trial whether a dose-reduction strategy to achieve an adequate dose of a FGA (5 mg/day haloperidol equivalents, n = 24) or switching to ziprasidone (160 mg/day, n = 24) in treatment resistant patients would decrease negative symptoms after 1 year of treatment. We found that negative symptoms did not change significantly in either condition. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference between conditions in favour of FGA dose reduction. Relapse and treatment failure, defined as a prolonged or repeated relapse, occurred more often with ziprasidone than with FGA (45.8% versus 20.8%, and 25.0% versus 16.7%, respectively). Treatment with ziprasidone was superior for extrapyramidal symptoms. Our study establishes that lowering high FGA doses to an equivalent of 5 mg/day haloperidol or switching to ziprasidone is feasible in the vast majority of patients but does not improve negative or other symptoms. Neither FGA dose reduction nor switching to ziprasidone is an adequate alternative to clozapine for long-stay patients with severe treatment resistant schizophrenia.

Prescription and Underprescription of Clozapine in Dutch Ambulatory Care.

Purpose: To our knowledge, no study has examined in a structured way the extent of underprescription of clozapine in ambulatory patients with Non-Affective Psychotic Disorder (NAPD). In the Netherlands, psychiatric care for such patients is provided by Flexible Assertive Community Treatment (FACT) teams and by early intervention teams. In 20 FACT teams and 3 early intervention teams we assessed the proportion of patients who: use clozapine (type 1 patients), previously used this drug (type 2), have an unfulfilled indication for this drug, by type of indication (type 3), or were at least markedly psychotic, but had not yet received two adequate treatments with other antipsychotic drugs (type 4). We expected to find major differences between teams. To rule out that these differences are caused by differences in severity of psychopathology, we also calculated the proportions of patients who use clozapine given an indication at any time (number of type 1 patients divided by the sum of type 1, 2, and 3 patients). Materials and methods: The nurse practitioner of each team identified the patients already on clozapine. Next, using a highly-structured decision tree, the nurse practitioner and psychiatrist assessed whether the remaining patients had an indication for this drug. Indications were treatment-resistant positive symptoms, tardive dyskinesia, aggression and suicidality. The severity of positive symptoms was determined using the Clinical Global Impression-Schizophrenia Scale (CGI-SCH). Results: In the participating FACT-teams 2,286 NAPD patients were assessed. The range among teams in proportions was: type 1: 8.8-34.7% (mean: 23.0%), type 2: 0-8.2% (mean: 3.5%), type 3: 1.7-15.6% (mean: 6.9%), type 4: 1.8-16.3% (mean: 8.6%). The range in proportions of patients using this drug given an indication was 49.0-90.9% (mean: 68.8%). These figures were lower in early intervention teams. Conclusions: The proportion of patients in FACT-teams who have an unfulfilled indication for clozapine is 6.9%. There were considerable differences between teams with respect to this proportion. Almost a third of the outpatients had at any time an indication for clozapine. If one takes type 4 patients into account, this proportion may be higher. Registration number: NTR5135 http://www.trialregister.nl/trialreg/index.asp.

Capillary compared to venous blood sampling in clozapine treatment: patients׳ and healthcare practitioners׳ experiences with a point-of-care device.

Underuse of the antipsychotic clozapine for schizophrenia is an impediment to improving outcomes for patients. Because of its possible severe side effects, including granulocytopenia or even agranulocytosis, clozapine treatment entails regular WBC monitoring, which can be a major drawback for patients and practitioners. The HemoCue WBC DIFF system is a point-of-care device using capillary blood sampling which provides WBC counts with differentials, including granulocytes. We investigated if capillary sampling instead of conventional venous sampling might diminish the burden for patients and practitioners and motivate them to continue clozapine treatment. A randomized cross-over trial design was used to compare the two sampling methods. Patients׳ subjective experiences of various aspects of blood sampling were rated on a 10-cm visual analogue scale (VAS). Patients and practitioners were also asked if they had any preference for venous or capillary sampling and patients were asked if the sampling method influenced their motivation to continue clozapine treatment. Seventy-three patients were included in this study. Three dropped out before completion. The VAS ratings on all five aspects and the total burden experienced showed a consistent pattern favouring capillary blood sampling (p<0.001). This pattern was more pronounced for inpatients than for outpatients. Patients strongly preferred capillary testing (p<0.001). The method used moderately influenced their motivation for clozapine therapy. In this study patients tolerated capillary blood testing with a point-of-care device better than traditional venous sampling at a laboratory and practitioners also preferred it. Using this method might therefore boost clozapine prescription rates.