Efficacy In Treatment-resistant Schizophrenia Research Articles

Predictors of clozapine efficacy in treatment-resistant schizophrenia: A cross-sectional analysis of sociodemographic, clinical, biochemical, and electrophysiological EEG changes

Predictors of clozapine efficacy in treatment-resistant schizophrenia: A cross-sectional analysis of sociodemographic, clinical, biochemical, and electrophysiological EEG changes

Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells.

The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5-20 µM) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30-40% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival.

Improving outcome of treatment-resistant schizophrenia: effects of cognitive remediation therapy.

Treatment-Resistant Schizophrenia (TRS) represents a main clinical issue, associated with worse psychopathological outcomes, a more disrupted neurobiological substrate, and poorer neurocognitive performance across several domains, especially in verbal abilities. If cognitive impairment is a major determinant of patients' functional outcomes and quality of life, targeting cognitive dysfunction becomes even more crucial in TRS patients in order to minimize cognitive and functional deterioration. However, although Cognitive Remediation Therapy (CRT) represents the best available tool to treat cognitive dysfunction in schizophrenia, specific evidence of its efficacy in TRS is lacking. Based on these premises, our study aimed at investigating possible differences in CRT outcomes in a sample of 150 patients with schizophrenia, stratified according to antipsychotic response (TRS vs. non-TRS). Subjects were assessed for neurocognition through Brief Assessment of Cognition in Schizophrenia (BACS) and the Wisconsin Card Sorting Test (WCST) at baseline and after CRT. As expected, we observed greater baseline impairment among TRS patients in BACS-Verbal Memory and WCST-Executive Functions. Repeated measures ANCOVAs showed significant within-group pre-/post-CRT differences in the above-mentioned domains, both among non-TRS and TRS subjects. However, after CRT, no differences were observed between groups. This is the first study to indicate that CRT represents a highly valuable resource for TRS patients, since it may be able to fill the cognitive gap between treatment response groups. Our finding further highlights the importance of early implementation of CRT in addition to pharmacotherapy to reduce the cognitive and functional burden associated with the disease, especially for TRS patients.

Safety aspects during treatment with clozapine. : Monitoring and rechallenge - a narrative review

Due to its unique efficacy in treatment-resistant schizophrenia, discontinuation of treatment with clozapine is frequently associated with asignificant worsening of symptoms, but also with an increased risk of suicide. Based on the literature, this review aims at summarizing different monitoring recommendations in order to be able to continue this therapy despite the occurrence of side effects. In addition, we provide recommendations when rechallenge of apreviously stopped treatment with clozapine can be considered and when adefinite discontinuation must take place. Medline, the Guideline for the use of clozapine 2013 of the Netherlands Clozapine Collaboration Group, and the S3Guideline for Schizophrenia of the German Association of Psychiatry, Psychotherapy and Psychosomatics were searched for relevant literature, the last query dating from April28th, 2023. If agranulocytosis or cardiomyopathy develops, treatment with clozapine must be discontinued and should not be resumed thereafter. In contrast, treatment with clozapine which had to be discontinued due to myocarditis or prolongation of the QTc interval may be continued if left ventricular function is normal or after normalization of the QTc interval. Other side effects are usually not absolute contraindications for rechallenge but often require the adjunctive use of additional pharmacologic and non-pharmacologic measures. Taking into consideration various monitoring recommendations, cessation of treatment with clozapine can often be prevented or treatment with clozapine that has been discontinued due to side effects can be resumed.

A Reactive Metabolite of Clozapine Induces Hematopoietic Toxicity in HL-60 Cells Undergoing Granulocytic Differentiation through Its Effect on Glutathione Metabolism.

Clozapine is an atypical antipsychotic with several advantages over conventional antipsychotics, in addition to its well-known efficacy in treatment-resistant schizophrenia. However, the high risk of agranulocytosis associated with clozapine therapy limits its clinical application. Clozapine bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in cytotoxicity toward neutrophils. Clozapine affects myeloid precursor cells rather than neutrophils; however, the impact of its reactive metabolite on myeloid precursor cells undergoing granulocytic differentiation remains unclear. Herein, we used hydrogen peroxide (H2O2) to generate the reactive metabolite and compared reactive metabolite-induced cytotoxicity between HL-60 cells undergoing granulocytic differentiation and differentiated HL-60 cells. In addition, we examined the role of oxidative stress in this type of cytotoxicity. The reactive metabolite of clozapine induced rapid cytotoxicity in HL-60 cells undergoing granulocytic differentiation, but not in differentiated HL-60 cells, with the metabolite exhibiting more potent cytotoxicity than clozapine. No cytotoxicity was observed following incubation with olanzapine, a structural analog of clozapine, even after exposure of the drug to H2O2. The reactive metabolite of clozapine decreased the levels of reduced glutathione, while addition of reduced glutathione attenuated the reactive metabolite-induced cytotoxicity. These findings indicate that glutathione metabolism plays a role in the hematopoietic toxicity induced by the reactive metabolite of clozapine. Oxidative stress may potentially increase susceptibility to the hematopoietic toxicity induced by the reactive metabolite of clozapine.

Diabetes mellitus prevalence in Northland New Zealand schizophrenia patients on clozapine.

Clozapine is a unique atypical anti-psychotic agent with best efficacy for treatment resistant schizophrenia compared to other agents, but with increased metabolic adverse effects. We sought to audit the prevalence of diabetes and pre-diabetes in Northland, New Zealand patients on clozapine. We captured all 287 patients in Northland, New Zealand who were prescribed clozapine in September 2021 and obtained demographic, clinical and laboratory data. We discovered that 26.48% had diabetes (one patient type one, 75 type two diabetes) and 14.63% had pre-diabetes that developed after a median of six years' clozapine treatment. Diabetes prevalence is approximately 6% in the general population. NZ Māori made up 65.85% of the entire cohort (35.8% of the general population) and 85.53% of the diabetes patients. NZ Europeans represented most of the remaining 30.66% on clozapine, consistent with the largely bicultural ethnic mix of our region. Māori on clozapine were younger: mean age 42 years, compared to NZ Europeans, mean age 49 years. The average BMI was 37kg/m2 for Māori, 32 for Europeans (range 21-63, SD 8); there was a moderate relationship between clozapine use and increasing BMI (correlation coefficient of 0.74). For the diabetes patients, glycaemic control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41-117). Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of Northland, New Zealand people with treatment-resistant schizophrenia on clozapine are required to reduce the 41% rate of dysglycaemia in this predominantly Māori group.

Prescribing clozapine in the UK: Quality improvement issues identified by clinical audit.

Introduction:The Prescribing Observatory for Mental Health initiated a quality improvement (QI) programme on clozapine use in UK mental health services.Methods:Clinical audits conducted in 2019 and 2021.Results:Sixty-three participating NHS Trusts/healthcare organisations in 2019, and 61 in 2021, submitted treatment data for 6948 and 8155 patients, respectively. In both audits, high-dose and/or combined antipsychotic medications had been prescribed immediately before initiating clozapine in over a quarter of patients recently started on clozapine. In patients who were tobacco smokers and recently discharged from a smoke-free ward, the impact of the potential change in smoking status had been considered in the care plans of just under one-third in 2019 and just over a half in 2021. For community patients, their Summary Care Records (SCRs) included their clozapine prescriptions in 58% of cases in 2019 and 72% in 2021.Conclusions:Three QI issues were identified. (1) Antipsychotic regimens with limited evidence for efficacy in treatment-resistant schizophrenia were prescribed for over a quarter of cases before starting clozapine. Use of such strategies may delay clozapine treatment, potentially reducing the likelihood of a therapeutic response. (2) While anticipation of the consequences of a change in smoking status on plasma clozapine concentration following discharge from hospital showed improvement over time, even in 2021 it was not evident for nearly a half of relevant cases. (3) While inclusion of clozapine in the SCR also improved over time, even in 2021 it was missing for more than a quarter of community patients.

Free Papers Compiled

Background:Clozapine is considered the antipsychotic of choice for patients with Treatment-Resistant Schizophrenia (TRS). Despite its proven efficacy in TRS, around 40–70% of patients have a poor response to clozapine. Limited numbers of studies have assessed the predictors of clozapine non-response.Objective:This study aims to assess the demographic and clinical factors associated with an inadequate response to clozapine in patients with TRS.Methods:287 outpatients with TRS receiving clozapine for more than one year were divided into two groups based on the need for a second antipsychotic medication and/or electroconvulsive therapy after receiving clozapine in the maximum tolerable dose for at least 3 months.Results:One-hundred and two (35.4%) of the patients were considered to have inadequate response to clozapine. Compared to responders, clozapine non-responders were unemployed at the time of starting clozapine (p=0.04), had a higher duration of untreated psychosis (p=0.007), had received significantly higher number of adequate trials in the past (p=0.02), were treated with polypharmacy in the past (p=0.01), had experienced adverse effects of first (p<0.001) and second-generation antipsychotics (p=0.01), and had more medical comorbidities (p=0.03). The non-responders more frequently had visual hallucinations (p=0.001), and made act (p=0.04) in the lifetime, and had a significantly higher CGI score at the time of starting of clozapine (p<0.001). While on Clozapine, non-responders received significantly higher dose of clozapine (p=0.001) and experienced more constipation (p=0.04), hypersalivation (p=0.002) and obsessive compulsive symptoms (p=0.05).Conclusions:The present study shows that about one-third of the patients with TRS do not respond to clozapine. However, clozapine non-responders, though broadly similar in socio-demographic profile, differ on past treatment profile.

Changes in Brain Glutamate on Switching to Clozapine in Treatment-Resistant Schizophrenia.

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks after switching from a non-clozapine antipsychotic to treatment with clozapine as part of their normal clinical care. Proton magnetic resonance spectroscopy (1H-MRS) measured concentrations, corrected for voxel tissue content, of glutamate (Glucorr), and glutamate plus glutamine (Glxcorr) in the anterior cingulate cortex (ACC) and right caudate nucleus. Symptoms were monitored using the Positive and Negative Syndrome Scale (PANSS). Of 37 recruited patients (27 men, 39.30 years old, 84% clozapine naïve), 25 completed 1H-MRS at both timepoints. 12 weeks of clozapine was associated with a longitudinal reduction in Glucorr in the caudate (n = 23, F = 7.61 P = .01) but not in the ACC (n = 24, F = 0.02, P = .59). Percentage reduction in caudate Glucorr was positively correlated with percentage improvement in symptoms (total PANSS score, n = 23, r = .42, P = .04). These findings indicate that reductions in glutamate in the caudate nucleus may contribute to symptomatic improvement during the first months of clozapine treatment.

Clozapine treatment: Ensuring ongoing monitoring during the COVID-19 pandemic.

The current coronavirus pandemic (COVID-19) has led mental health systems to uncertainty regarding safe continuation of clozapine monitoring protocols. Clozapine is without doubt the only antipsychotic available with repeatedly proven efficacy in treatment resistant schizophrenia.1 Replacing clozapine with an alternative antipsychotic in patients stabilized with clozapine can potentially lead to higher risk of relapse or exacerbation of severity of illness.1 Clozapine, as already known, has a number of side effects, some of which can be serious, thus patients receiving clozapine require ongoing scheduled monitoring. Side effects of clozapine include neutropenia or agranulocytosis, myocarditis, fever, hypersalivation, weight gain and constipation. These side effects can be detected and treated when recognized on time decreasing the possibility of serious consequences making the implementation of an ongoing treatment monitoring protocol for patients on clozapine mandatory.2 Since it was advised for all mental health providers in most countries worldwide to limit non-urgent hospital visits and procedures to reduce the risk of contamination a challenge arose for patients' ability to access health care facilities for their routine clozapine monitoring. Nevertheless, the majority of Mental Health Care Authorities decided to ensure access for all patients on clozapine to their routine monitoring protocol.3,4 To date, no data exist on any potential relationship between antipsychotic use and the risk of contamination with SARS-CoV-2 or the development of severe symptoms of the infection. The literature suggests that patients receiving antipsychotics, especially clozapine, have an increased risk of developing pneumonia, leading to the assumption that patients receiving clozapine are at higher risk to develop COVID-19. 1 Balancing the importance of monitoring continuation against the increased risk for COVID-19, an International Consensus Statement was recently published addressing a monitoring protocol with reduced visits. The Consensus suggested reduced hematologic monitoring frequency of every 3 months with a prescription of 90 days clozapine supply (if safe). The above applies to patients receiving clozapine for at least one year without neutropenia. Τhe risk of neutropenia after 12 months of clozapine treatment falls significantly.4 Based on the above it is suggested to all clozapine clinics to implement a guidance monitoring protocol for all patients on clozapine to ensure safety during the pandemic. Besides hematological monitoring that requires physical contact with healthcare workers it is significant to implement a telemedicine appointment in frequent intervals to monitor symptoms of infection, symptoms of cardiovascular diseases and constipation. Patient should also be advised to regularly monitor one's blood pressure and pulses and ideally be educated on how by a member of the staff. If a patient is detected with any symptoms related to the above an emergency appointment for evaluation should be planned. Overall, since both the consequences and the duration of the pandemic are unknown, mental health services must work jointly to implement a clozapine monitoring plan to ensure safe continuation in such a vulnerable population.

M215. FACTORS ASSOCIATED WITH CLOZAPINE RESPONSE AND RESISTANCE IN SCHIZOPHRENIA

BackgroundClozapine remains the only antipsychotic with unique efficacy in treatment resistant schizophrenia (TRS). Considerable ongoing research and clinical efforts have focused on reducing barriers to clozapine use in a bid to increase rates of clozapine use to improve outcomes in TRS. However, less than half of individuals with TRS respond to clozapine, with the remainder categorised as clozapine resistant (CRS) or Ultra-resistant. It is important to deepen understanding on the development of CRS so we can identify them early, attempt to prevent/delay its onset and also explore novel treatments. In the present study, we sought to compare clozapine responders from CRS and identify factors which might be associated with CRS.MethodsThis study was conducted at the Institute of Mental Health, the only psychiatric facility with clozapine services in Singapore. Individuals with TRS on clozapine for at least 12 weeks and the capacity to give informed consent were enrolled into the study. Each participant underwent a clinical assessment on the Structured Clinical Interview DSM-IV-TR (SCID), Positive and Negative Syndrome Scale (PANSS) and Social Occupational Functioning Assessment Scale (SOFAS). We applied the Treatment Response and Resistance In Psychosis consensus criteria to define clozapine response and resistance. Brief Neurocognitive Assessment was done using the digit sequencing and symbol coding tasks from the Brief Assessment of Cognition in Schizophrenia (BACS). A fasting sample of blood was collected; assays for clozapine and norclozapine were performed using high performance liquid chromatography. To be classified as CRS, a participant must meet the below criteria: (i) not meeting symptom remission criteria on the PANSS using the Remission in Schizophrenia Working Group criteria, (ii) moderate and lower level of functioning on the SOFAS, and (iii) at least 12 weeks of clozapine treatment and plasma clozapine levels ≥ 350 ng/ml.ResultsA total of 91 participants were enrolled in this study and 67 (73.6%) met criteria for CRS. 1 in 4 clozapine responders had plasma clozapine levels not exceeding 350 ng/ml. There were no significant differences in age, sex, smoking status, age at onset of illness, clozapine adherence, antipsychotic polypharmacy rates and duration of clozapine use between clozapine responders and CRS. Compared to clozapine responders, individuals with CRS had statistically significantly lower BMI (26.4 vs. 23.4, p=0.008) lower rates of employment (79.2% vs. 35.8%, p<0.001), and poorer cognitive function in both digit sequencing (-0.86 vs. -1.60, p=0.011) and symbol coding (-1.09 vs. -1.88, p=0.002) tasks. In a multivariate logistic regression model with age, sex, age at onset, BMI and cognition, only BMI (OR=0.88, p=0.043) and symbol coding (OR=0.48, p=0.019) were significant variables predicting clozapine resistance.DiscussionOur study highlighted a high rate of CRS and suggests that poorer cognitive function, specifically in processing speed, might be associated with the development of clozapine resistance in schizophrenia. Additionally, it was interesting to note that a higher BMI was associated with clozapine response; this lends weight to existing metabolic and lipid hypotheses of schizophrenia.

Rechallenge of clozapine in a patient with a history of clozapine-induced myocarditis

Clozapine is the only antipsychotic with proven efficacy in treatment-resistant schizophrenia, but some life-threatening side effects limit its use. Here we report a patient with clozapine-induced myocarditis and successful rechallenge. The patient still uses clozapine and has not developed myocarditis over 36 months of observation. It may be possible to use clozapine even after myocarditis and thus improve symptoms and functionality of schizophrenia patients.

Addressing clozapine under-prescribing and barriers to initiation: a psychiatrist, advanced practice provider, and trainee survey.

Clozapine use has declined, despite its superior antipsychotic efficacy in treatment-resistant schizophrenia. Implications for clozapine underutilization include suboptimal treatment outcomes and increased hospitalizations. Many barriers preventing the use of clozapine have been described in the literature, including suboptimal knowledge and poor perceptions. The aim of this study was to assess psychiatry prescribers' perception and knowledge of clozapine. A survey was distributed to advanced practice providers, psychiatrists, and trainees (i.e. residents and fellows) at 10 medical centers within the US and Canada. The survey asked respondents about their perception of clozapine use and assessed their pharmacotherapeutic knowledge of clozapine. Two hundred eleven individual submitted completed surveys of a possible 1152; a response rate of 18.3%. There were no statistically significant differences between the advanced practice provider plus psychiatrist groups and the trainee group for most perception (eight of nine) and knowledge (eight of nine) questions. The knowledge questions with the lowest scores pertained to clozapine reinitiation and myocarditis. The majority of all respondents (144, 68.2%) felt that clozapine prescribing was a burden. Findings of this study support the need for continued clozapine education regardless of a prescriber's age/experience. Future studies to assess barriers to clozapine prescribing should extend beyond academic centers.

A case report of the successful administration of clozapine in the face of myocardial infarction, pulmonary embolism and hyperlipidaemia resulting in the termination of long-term seclusion

BackgroundCardiometabolic health significantly impacts on the mortality of people with severe mental illness. Clozapine has the greatest efficacy for Treatment Resistant Schizophrenia (TRS) but the greatest negative impact on cardiometabolic health. Balancing the risks and benefits of treatment, dignity, autonomy, liberty, mental and physical health can be challenging, particularly when imposing interventions with potentially life threatening adverse events, such as clozapine. We describe the successful administration of clozapine in the face of myocardial infarction, pulmonary embolism and hyperlipidaemia resulting in the termination of long-term seclusion for a gentleman with TRS in high secure psychiatric services.Case presentationThe impact of clozapine on a 44-year-old gentleman with TRS, extreme violence requiring physical restraint and long-term segregation, and numerous other significant physical health complications is described. He had metabolic syndrome; a poor diet, sedentary lifestyle, Body Mass Index (BMI) of 31.5, poorly controlled lipids and had smoked heavily since childhood. During preparations to initiate clozapine, he suffered a myocardial infarction and pulmonary embolism. His compliance with secondary prevention medications was poor due to paranoid persecutory and somatic delusions. Despite these concerns, nasogastric administration of clozapine was approved and prescribed within nine months of his myocardial infarction and a month from his pulmonary embolism but was ultimately not required. Accepting oral medication, his mental state made a rapid and dramatic improvement. After spending 1046 days in seclusion, this was terminated 94 days after clozapine initiation. He has been compliant with all medications for 24 months, had no incidents of violence or seclusion, and has been transferred to medium secure services. His physical health stabilised despite continuing to lead a sedentary lifestyle and remaining obese (BMI of 35). He developed hypertension, Type II Diabetes Mellitus and his triglycerides rose to 22.2 mmol/L in the same month after clozapine initiation. However, with pharmacological intervention, 24 months later these are controlled, and he has had no further thromboembolic events.ConclusionsWe highlight that despite significant physical health concerns, clozapine can be successfully initiated and safely prescribed with a significantly positive effect on both the psychiatric and holistic care of patients with treatment resistant schizophrenia.

Biological Predictors of Clozapine Response: A Systematic Review.

Background: Clozapine is the recommended antipsychotic for treatment-resistant schizophrenia (TRS) but there is significant variability between patients in the degree to which clozapine will improve symptoms. The biological basis of this variability is unknown. Although clozapine has efficacy in TRS, it can elicit adverse effects and initiation is often delayed. Identification of predictive biomarkers of clozapine response may aid initiation of clozapine treatment, as well as understanding of its mechanism of action. In this article we systematically review prospective or genetic studies of biological predictors of response to clozapine.Methods: We searched the PubMed database until 20th January 2018 for studies investigating “clozapine” AND (“response” OR “outcome”) AND “schizophrenia.” Inclusion required that studies examined a biological variable in relation to symptomatic response to clozapine. For all studies except genetic-studies, inclusion required that biological variables were measured before clozapine initiation.Results: Ninety-eight studies met the eligibility criteria and were included in the review, including neuroimaging, blood-based, cerebrospinal fluid (CSF)-based, and genetic predictors. The majority (70) are genetic studies, collectively investigating 379 different gene variants, however only three genetic variants (DRD3 Ser9Gly, HTR2A His452Tyr, and C825T GNB3) have independently replicated significant findings. Of the non-genetic variables, the most consistent predictors of a good response to clozapine are higher prefrontal cortical structural integrity and activity, and a lower ratio of the dopamine and serotonin metabolites, homovanillic acid (HVA): 5-hydroxyindoleacetic acid (5-HIAA) in CSF.Conclusions: Recommendations include that future studies should ensure adequate clozapine trial length and clozapine plasma concentrations, and may include multivariate models to increase predictive accuracy.

F94. A PREVALENCE PILOT STUDY FOR OBSTRUCTIVE SLEEP APNEA SYNDROME IN CLOZAPINE USERS

BackgroundObstructive Sleep Apnea Syndrome (OSAS) is a frequent and common disorder. Estimated 50.000 persons in the Netherlands suffer from this disorder. Clozapine is known for its efficacy in treatment resistant schizophrenia. Frequent side effects of clozapine are weight gain, fatigue, sleepiness and metabolic syndrome. Similar symptoms occur in the course a OSAS. The Dutch pharmacovigilance centre LAREB (LAREB 2012) proposed an association between OSAS and clozapine usage, independent of confounding factors as obesity, smoking and glucose intolerance. Although clozapine is much used in the treatment of schizophrenia, OSAS prevalence studies in the clozapine treatment group are scarce. Research is needed to elucidate the relationship between clozapine use and OSAS. Identifying OSAS and treatment with continuous positive airway pressure (CPAP) could possibly (Galletly te al, 2016), through reduction in cardiovascular risk factors, have a favorable effect on mortality and possibly have a positive effect on daytime sleepiness, fatigue and daytime functioning.Primary goal of this study is discovering the prevalence of OSAS in clozapine using schizophrenic spectrum disorder patients. The secondary goal is discovering how willing schizophrenic spectrum disorder patient are in undergoing a polysomnography.HypothesisMany patients with schizophrenia spectrum disorder have multiple OSAS risk factors: obesity, presence of metabolic syndrome, frequent usage of benzodiazepines, male sex, older age. OSAS prevalence is estimated to be much higher than in the general population because of these risk factors. Atypical antipsychotics are an independent risk factor for the development of OSAS. Polysomnographically diagnosed OSAS will even be higher in the clozapine treatment group estimated to be present in 30% percent of the patients.MethodsResearch design: prospective observational and cross-sectional study in a group of stable adult patients with DSM IV schizophrenia spectrum disorder treated with clozapine in an outpatient community mental health service. Estimated study group consists of 30–50 patients. Exclusion criteria: unwillingness to undergo a polysomnography, inability to give informed consent, insufficient understanding of the Dutch language, severe cardiac failure, a history a cerebrovascular accidents and alcohol abuse.Methodscreening on the presence of OSAS symptoms and risk factors associated with OSAS through: Epworth Sleepiness Scale for daytime sleepiness (Johns, 1991), STOP-BANG Questionaire ((SBQ: Chung 2012) when there is a high risk for OSAS followed by an ambulatory polysomnography including heart rate/ECG, respiratory measures with nasal flow canule and thermistor flow inductive respiratory movements, oximetry, and snoaring noises through sensory measurements (AASAM, 2009). OSAS is considered to be present in the presence of daytime sleepiness and if the Apnea Hypopnea Index (AHI) is larger than 5.0 obstructive or mixed type respiratory events per hour (AASM, 2009: Berry et. al, 2015: NVALT & CBO, 2009).Statistical analysis: polysomnography: descriptive and univariate analysis. Presence of OSAS will be dichomotized (1 =OSAS present; 0 = OSAS absent) Summation of the amount of positive results will be presented as percentage of the total study population. Chi- squared test for considering of the height of the results on the ESS test and the STOP-Bang test and the prevalence of OSAS. Statistical significance: p < 0.05.Prevalence: percentage of patients in the clozapine treatment group with OSAS.ResultsNo results at the moment of poster submission. In April 2018 results will be presented.DiscussionWill be presented in April 2018.

Effect of clozapine on psychiatric comorbidities in patients with schizophrenia

IntroductionClozapine has superior efficacy in treatment-resistant schizophrenia, and has various effects on psychiatric comorbidities, which may affect the illness course.AimsWe aimed to assess the past and current psychiatric comorbidities in schizophrenia patients treated with clozapine, and study their relationship with clinical variables.MethodsConsecutive 122 outpatients who met DSM-IV criteria for schizophrenia receiving clozapine were included. Information about past and current clinical status were gathered through a clinical interview and review of the medical records, along with laboratory test results. Patients were assessed with structured clinical interview for Axis-I Disorders for DSM-IV, Clinical Global Impression Scale, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Panic and Agoraphobia Scale (PAS), WHO-Disability Assessment Schedule-II.ResultsThere was a significant decrease in the diagnosis of depression, alcohol and substance use disorder, number of suicide attempts, and an increase in the diagnosis of obsessive compulsive disorder (OCD) after clozapine initiation. Clozapine related de novo OCD appeared in 48.4% of the patients, and there was a positive correlation between Y-BOCS total scores and clozapine dose and plasma levels. In the de novo OCD group, compulsion scores were higher than obsession scores with checking most prevalent among compulsions. Total PANSS, Y-BOCS, PASscores were positively correlated withtotal disability score.ConclusionsClozapine seems to decrease comorbid depression, alcohol and substance use and number of suicide attempts and increase OCD. Assessment and treatment of psychiatric comorbidities in clozapine using schizophrenia patients is vital to decrease disability.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Brain stimulation methods for patients with schizophrenia – new therapies on the horizon?

Summary Background: Non-invasive brain stimulation (NIBS) techniques offer new promising treatment options in schizophrenia. However, the evidence from meta-analyses and randomized clinical studies is limited. Results: For repetitive transcranial magnetic stimulation (rTMS) the clinical efficacy is highest for the 1-Hz rTMS over the left temporal cortex to improve auditory hallucinations, nevertheless there are studies showing no benefit. For negative symptoms rTMS could be offered keeping in mind the good tolerability. Transcranial direct current stimulation (tDCS) has a good risk-benefit ratio, but the evidence for schizophrenia symptoms is still derived from small sample studies. Electroconvulsive therapy (ECT) is the treatment option with the highest clinical efficacy for treatment-resistant schizophrenia, catatonia or other defined treatment circumstances, but has more adverse side effects. More research is needed to understand which stimulation technique could be recommended for a certain patient.

Clozapine for Schizophrenia: State Variation in Evidence-Based Practice

Clozapine is the only antipsychoticwith known efficacy in treatment-resistant schizophrenia. Although 20% to 30% of individuals with schizophrenia have treatment-resistant conditions, clozapine accounts for only about 5% of their antipsychotic starts (1).We updated our previous analysis (2001–2005) by examining more recent (2006–2009) trends and patterns across 46 state Medicaid programs. Overall, clozapine accounted for 4.8% (95% confidence interval [CI]54.8%–4.9%) of antipsychotic use in schizophrenia, with a slight decline during this period: 5.7% (CI55.6%–5.8%) in 2006; 4.9% (CI54.8%–5.0%) in 2007; 4.6% (CI54.5%–4.6%) in 2008; and 4.3% (CI54.2%–4.4%) in 2009. Figure 1 shows substantial interstate variation. Clozapine was least commonly used in the Deep South and more commonly used in New England, the Rocky Mountain West, and Washington. The highest rate was in SouthDakota (15.6%, CI514.0%–17.2%) and the lowest in Louisiana (2.0%, CI51.9%–2.2%). Fiscal stress has been linked to lower clozapine use (2), as has inadequate staffing to monitor clozapine (3). The state variations are broadly consistent with known variations in overall Medicaid spending for disabled beneficiaries. Patient reluctance about blood monitoring and concerns over tolerability are unlikely to explain the variation. These findings underscore the need to determine the extent to which state variation can be explained by local practice environments or state policy factors. Interventions and policies are needed to promote appropriate clozapine treatment of Medicaid-insured patients with treatment-resistant schizophrenia.

Genome-wide association study of lymphoblast cell viability after clozapine exposure.

Clozapine is an antipsychotic drug with proven efficacy in treatment-resistant schizophrenia but also known to induce potentially lethal agranulocytosis (CIA) in 1% of patients. Genetic factors are likely to play a role in the molecular basis of CIA. We explored an in vitro system to study the genetic susceptibility of CIA. Cell viability was measured in 90 lymphoblast cell lines exposed to a series of increasing concentrations of clozapine for 48 hr. Quantitative trait measures of cell viability as well as area under the survival curve were used in a linear mixed model for genome-wide association analyses. The estimated heritability of clozapine-induced cell viability reduction in these cell lines is h2=0.76. No genome-wide significant association was observed after correction for multiple testing. Two independent loci with nominal evidence of association were observed at 30× clinical clozapine concentration: rs2709505 (P=1.41×10(-8)) in an intron of MDFIC and rs10457252 (P=1.79×10(-8)) located in a gene desert at chromosome 6q21. We identified one locus (rs1293970) near PRG4 that was consistently associated for all separate concentration analyses at P<5×10(-5). PRG4 encodes hemangiopoietin, a growth stimulator for hematopoietic stem cells. No evidence was observed for involvement of the MHC region. Our results demonstrate that clozapine-induced viability reduction in lymphoblast cell lines is a heritable, polygenic trait. Thus, in vitro models of CIA might be a useful tool for future discovery of genetic risk factors, although larger sample sizes will be required to unambiguously identify these loci.