Management Of Treatment-resistant Schizophrenia Research Articles

Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study.

The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity. A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire. Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively. Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.

Clozapine clinical toolkit optimizes inpatient clozapine monitoring.

Clozapine is the most effective antipsychotic in the management of treatment-resistant schizophrenia; however, its use is challenging due to the risk of severe adverse effects. Despite the risks associated with clozapine, there is no mandatory monitoring in Canada beyond hematologic testing for agranulocytosis surveillance. This study focuses on the development, implementation, and evaluation of a clozapine clinical toolkit (CTK) targeted at optimizing inpatient clozapine use. A comprehensive literature review was conducted to identify clozapine best practices, experts were consulted, and a comprehensive clozapine CTK was developed and implemented at a large Canadian tertiary hospital in December 2018. To evaluate the CTK, a retrospective chart review was conducted to assess for change in guideline-concordant monitoring pre- and post- CTK implementation. Patients were included if they were > 18 years of age and received clozapine during inpatient admission. Results were analyzed using descriptive and inferential statistics. Among the charts reviewed, 185 and 113 admissions met the pre- and post-CTK inclusion criteria, respectively. Staff used the CTK in the care of 96% of clozapine patients post implementation, and its use resulted in improvements in guideline-concordant monitoring for agranulocytosis and myocarditis. Implementation of the clozapine CTK increased the concordance of clozapine monitoring with best practice recommendations. Future research is necessary to assess the impact of the CTK on clinical outcomes and patient satisfaction.

Management of Treatment-Resistant Schizophrenia in a Patient With Epilepsy With Add on Low-Dose Clozapine-A Case Report.

Management of Treatment-Resistant Schizophrenia in a Patient With Epilepsy With Add on Low-Dose Clozapine-A Case Report.

Clozapine-Induced Stuttering after a Seizure: About a Case Report

Clozapine is an atypical antipsychotic with proven efficacy in the management of treatment-resistant schizophrenia. It has well-documented side effects. Stuttering is defined as a disturbance in the normal functioning of fluency and temporal structuring of speech. In adulthood, it can occur because of various causes including the side effect of medications. Previous case reports have found that clozapine-induced stuttering can coexist. In this article, we describe a case in which stuttering following a generalized seizure was observed when increasing doses of clozapine.

Efficacy of Clozapine in Patients with Schizophrenia – A 3-Month follow-up Study from North India

Abstract Background: Treatment-resistant schizophrenia (TRS) is one of the most disabling forms of schizophrenia. The Indian population being different in its sociodemographic factors, clinical profiles, and family structures, the experience of the efficacy of clozapine here is insufficient. Aim: The aim of the study is to explore the efficacy of clozapine in TRS over 3 months of drug use. Materials and Methods: It was an open-label interventional 12-week follow-up study, with 30 consenting adults with TRS determined as per modified Conley and Kelly’s criteria of treatment resistance. The patient’s sociodemographic and clinical details were recorded. Oral clozapine was initiated with gradual up-titration after preclozapine workup. The Positive and Negative Syndrome Scale (PANSS) score was assessed at baseline and reviewed at 4 weekly intervals. Results: By the end of 12 weeks, on an average dose of 494 ± 113.83 mg/day, 36.67% of patients reported 25%–50% improvement in PANSS score. The maximum improvement was seen in the positive symptoms subscale followed by the general and negative symptoms subscale. Conclusion: This study enlightens the dosage differences and efficacy of clozapine in the management of TRS in the Indian population.

Combination of clozapine, cariprazine and fluoxetine in treatment-resistant schizophrenia patient with prominent negative symptoms: A Case report

IntroductionDespite pharmacological advances in the treatment of schizophrenia, significant number of patients are still treatment-resistant. Clozapine is recommended as first-line treatment for treatment-resistant schizophrenia (TRS) in guidelines. Despite the greater efficacy of clozapine over other antipsychotics in the management of TRS, a significant number of patients fail to attain adequate response or develop adverse effects, and more interventions are needed.ObjectivesTo describe a clinical case of treatment-resistant schizophrenia patient with prominent negative symptoms treated with combination of clozapine, cariprazine and fluoxetine, and to review the literature.MethodsClinical case presentation through review of the clinical file and non-systematic review on PubMed and ResearchGate.ResultsA 41 year old female patient presented to inpatient clinic with low mood, occasional commanding and commenting verbal hallucinations, occasional suicidal thoughts, blunted affect, anhedonia, asociality, she was apathetic, lacked motivation to get up from bed, had night’s sleep disturbance. Patient was diagnosed with Schizophrenia in 2009, she has been hospitalized in Psychiatric wards for 16 times. She has received treatment with combinations of several antipsychotic drugs and antidepressants, had side-effects and have not reached full remission. During treatment with clozapine (up to 175mg per day) in combination with cariprazine (up to 4.5mg per day) and fluoxetine (up to 20mg per day), gradually negative symptoms decreased, patient became more active, showed interest in daily and rehabilitation activities, night’s sleep improved.Conclusions Patient with treatment-resistant schizophrenia benefited from combination of clozapine, cariprazine and fluoxetine. Further research is necessary on treatment combination strategies for TRS.DisclosureNo significant relationships.

Haematological Monitoring in Clozapine Use: Blood Best Sampled in the Afternoon?

AimsClozapine is an atypical antipsychotic used in the management of Treatment-Resistant Schizophrenia (TRS). Despite its efficacy, Clozapine is associated with rare but clinically important haematological side effects of neutropenia and agranulocytosis, thus warranting regular monitoring of full blood count (FBC) white blood count (WBC) and neutrophil count (NC).Clozaril Patient Monitoring service (CPMS) supervises the prescribing of Clozapine and haematological testing for patients. Amber and Red alerts are issued by the CPMS when WBC and NC values fall below specified levels, Clozapine treatment is either suspended or discontinued completely.MethodsWe present a case of 35-year-old Caucasian lady with a history of schizophrenia who was maintained on Clozapine treatment for 10 years and whose Clozapine was necessarily stopped because of red alerts. This lead to a significant deterioration in her mental state and level of functioning necessitating a prolonged hospital admission.Results•Detailed retrospective review of this patient's CPMS results over a 2-year period identified consistently higher levels of WBC and NC, when the blood tests were conducted in the afternoon compared to mornings.•Literature review supported the phenomenon of a diurnal variation of WBC and NC levels in a proportion of patients prescribed Clozapine.•With clear knowledge of this patient's diurnal trends in WBC and NC count, it was possible to liaise with CPMS and restart her Clozapine treatment, leading to a significant improvement in her mental state and level of functioning.Conclusion•We recommend that clinicians consider this phenomenon of diurnal variation in blood parameters in patients with frequent amber and red alert results who are at risk of having their Clozapine medication discontinued.•Close collaboration with CPMS and haematological advice may lead to a more nuanced approach to blood sampling, whereby afternoon samples are used in certain at-risk patients.

Lubiprostone for the Treatment of Clozapine-Induced Constipation: A Case Series

Clozapine-induced constipation is an increasingly recognized adverse reaction that frequently impairs optimal management of treatment-resistant schizophrenia. The Food and Drug Administration recently strengthened an existing warning for clozapine, citing constipation as an adverse effect that can progress to serious bowel complications. Evidence-based guidelines for laxatives in the management of clozapine-induced constipation remain scarce, and there is a general need for improved algorithms in the management of this common condition. Lubiprostone is a relatively new laxative that has labeled indications for opioid-induced constipation, irritable bowel syndrome with constipation, and chronic idiopathic constipation. This case series describes clinical pearls associated with four cases of treatment-resistant schizophrenia who underwent treatment of clozapine-induced constipation with lubiprostone. The findings of this case series suggest that there may be significant therapeutic potential in the utilization of lubiprostone for the management of clozapine-induced constipation with a low risk of adverse reactions. The study of lubiprostone benefit (i.e., without coadministration of other laxatives) continues to be of prominent interest in understanding its ability to manage clozapine-induced constipation.

Biological variation in clozapine and metabolite reporting during therapeutic drug monitoring

BackgroundClozapine (CLO) is an atypical antipsychotic used in management of treatment-resistant schizophrenia. Adverse drug reactions are caused by both CLO and its primary metabolite, norclozapine (NCLO). We defined the biological variability of CLO, NCLO, and the CLO to NCLO ratio (CNR) as well as assess the impact of reporting CLO and NCLO routinely. MethodsThe CVi and CVg were calculated from 1904 results from 247 patients by CV-ANOVA, and ANOVA, respectively, for CLO, NCLO, and the CNR. Association between each were also analyzed against a number of parameters including age and gender, complete blood count (CBC), kidney and liver function tests, lipids, and glucose within 24 h of CLO measurement. ResultsFor CLO, NCLO and CNR, the CVi was calculated as 19.3%, 19.2%, and 14.7%, and the CVg was 46.9%, 51.4%, and 36.3%, respectively. A total of 87 patients (19.7%) demonstrated higher NCLO results than CLO, with a ratio as low as 0.47. Kidney function was also found to have a statistically significant relationship to CLO and NCLO levels. ConclusionsWe provide data for biological variability of CLO metabolism as well as while providing some evidence for reporting NCLO values clinically.

An evaluation of the prescribing of clozapine for treatment-resistant schizophrenia in one NHS Trust in England

Abstract Introduction As a merger of two trusts had occurred, and recent research on the impact of the delay of initiating clozapine (1), this study was initiated to investigate if NICE guidelines for the management of treatment-resistant schizophrenia (TR-SCZ) were followed. NICE recommends that clozapine is offered after a trial of two antipsychotics drugs of appropriate dose and duration. The risk of potentially fatal side effects and the need for regular blood monitoring can deter patients and prescribers in initiating clozapine at an earlier stage (1). Aim To evaluate the prescribing of clozapine in patients with TR-SCZ in a large NHS trust against NICE guidelines. Methods Due to a fixed project time scale of 3 months, the medical records of 20 patients with TR-SCZ were accessed in November 2019 in order to determine compliance with NICE guidelines. Inclusion criteria for the study included a diagnosis of TR-SCZ in patients over 18 but under 60 years-old and a first attempt of prescribing clozapine after 2017. The records were analysed to establish how many antipsychotics were prescribed before clozapine was initiated, the number of patients remaining on clozapine after nine months, and the reason for stopping (where appropriate). A collection tool was created in Excel and data was analysed using descriptive statistics. Results All 20 patients had tried at least two antipsychotics, with 75% (n=15) having tried more than two before the initiation of clozapine. The mode number of antipsychotics prescribed was three. At the point of data collection, 75% (n=15) of the patients remained on clozapine. Of the five patients no longer taking clozapine, three patients remained on it for more than nine months before it was stopped. Documented reasons for stopping included side effects (neutropenia (n=1) and tachycardia (n= 1)) and patient choice (n=3). Conclusion Clozapine is an effective treatment for TR-SCZ (1), (2). This is backed up by the majority of patients in this study remaining on the treatment after nine months. This study also agrees with previous research (1) indicating guidelines for prescribing clozapine are not followed. 75% of patients were prescribed more than the recommended two antipsychotics before clozapine was initiated. However, the patient notes did not indicate the reasons for using more than two other antipsychotics before trialling clozapine or impact of the delay of its initiation. It would therefore be prudent for future research to determine the reasons for and impact of prescribing clozapine after more than two other antipsychotics had been trialled. References (1) Shah P, Iwata Y, Plitman E, Brown EE, Caravaggio F, Kim J, Nakajima S, Hahn M, Remington G, Gerretsen P, Graff-Guerrero A. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: a systematic review. Psychiatry research. 2018 Oct 1;268:114-22. (2) National Institute for Health and Care Excellence. Psychosis and schizophrenia: treatment and management. (Clinical guideline 178.) c2014. [Updated 2021; cited 2021 Oct 14]. Available from: http://guidance.nice.org.uk/CG178

Association between the examination rate of treatment-resistant schizophrenia and the clozapine prescription rate in a nationwide dissemination and implementation study.

BackgroundThe decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment‐resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine.MethodsAfter attending a 1‐day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty‐nine facilities in 2017 were included in the study.ResultsThere were dichotomous distributions in the examination rate of TRS and a non‐normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (r s = 0.531, P = 1.032 × 10−4). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS.ConclusionAs a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families.

Clozapine prescribing barriers in the management of treatment-resistant schizophrenia: A systematic review.

Treatment-resistant schizophrenia is prevalent and difficult to manage, as patients fail multiple antipsychotic trials before being considered as treatment-resistant. Currently clozapine is the only Food and Drug Administration-approved pharmacotherapy for treatment-resistant schizophrenia but remains under-prescribed. The purpose of this study is to investigate recent literature on clozapine in order to identify barriers to prescribing clozapine and categorize the recommended solutions. We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Using free text and the medical subject headings, we searched MEDLINE/PubMed electronic bibliographic database from 2017 until 2020. Eligible studies included peer-reviewed English language articles with multiple methodologies aiming to identify clozapine barriers in treatment-resistant schizophrenia. We used search terms combining clozapine AND treatment OR treatment-resistant schizophrenia AND barriers AND prescribing OR prescription OR prescriber. We merged search results in a citation manager software, removed duplicates, and screened the remaining articles based on the study eligibility criteria. We retrieved 123 studies, however, only 10 articles exclusively met the study inclusion criteria for full text review. These studies represented 20 countries; 6 were exclusively conducted in the US. The top barriers delineated by the studies include: providers' lack of knowledge and training (n = 7), concern about side effects (n = 8), and poor adherence (n = 7). All studies described more than 1 barrier. Other barriers included prescriber-perceived barriers (n = 4), administrative barriers (n = 5), and other healthcare systems-related barriers (n = 3). Top recommendations to overcome clozapine prescription barriers included improving prescriber clozapine education/training, utilizing interdisciplinary teams and providing integrated care via clozapine clinics, and simplifying blood test monitoring. Clozapine remains under-prescribed for patients with treatment-resistant schizophrenia due to multiple barriers related to the individual prescriber, system of care, and technology. It is recommended that by improving prescriber knowledge and training, use of integrated care, and use of technology that can enable continuous, real-time blood test monitoring, these barriers may be overcome.

A Guideline Review on Treatment-Resistant Schizophrenia: A Focus on Clozapine and other Pharmacotherapeutic Strategies

Background: Treatment-Resistant Schizophrenia (TRS) represents a significant challenge in mental health provision. Although underused in clinical practice, clozapine remains the treatment of first choice for TRS. This review aims at reviewing clozapine and other treatment options for TRS as recommended in the most recent schizophrenia Clinical Practice Guidelines (CPGs). Methods: A literature search for CPGs was undertaken in four electronic databases, using the terms: ‘schizophrenia’, ‘clozapine’ and ‘guidelines’. Results: Seven schizophrenia CPGs published by national or professional institutions were identified from the period of 2010-2020. The CPGs varied in the scope of the information provided about clozapine’s role in the management of schizophrenia. However, they provided strong supporting evidence on its efficacy in the management of TRS. Main differences in recommendations provided in the schizophrenia CPGs were in relation to the definition of TRS, on the management of patients with TRS who do not respond to clozapine treatment, and on the breath of information in relation to clozapine’s safety profile and monitoring recommendations. Conclusions and Recommendations: Future iteration of schizophrenia CPGs should address these important gaps in information, including strategies to support the safe use of clozapine to decrease treatment delays and reluctance in the use of this effective medication.

Augmentation strategies for treatment-refractory clozapine patients

BackgroundClozapine can be a life-saving and course-altering treatment for patients with psychosis, particularly treatment-resistant schizophrenia. Unfortunately, clozapine monotherapy rarely leads to a full symptomatic remission.AimsThis talk outlines key decision points in the use of clozapine: how to select patients for clozapine treatment and how to optimize clozapine’s efficacy in patients with a poor response to an adequate clozapine monotherapy trial.ConclusionsClozapine’s main indication is for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) should be used to optimize clozapine dosing during a clozapine trial and to rule-out pseudo-resistance. Up to 50% of patients do not respond to clozapine monotherapy and augmentation strategies can be utilized in such cases. Pharmacological add-on treatments are selected based on the most prominent symptom cluster (refractory psychosis, negative symptoms, depression and suicidality, aggression). Electroconvulsive therapy is the most effective augmentation strategy for refractory psychosis and suicidality. Non-pharmacological interventions and a focus on quality of life become important considerations in clozapine non-responders.CommentsClozapine is an important and underutilized tool in the management of treatment-resistant schizophrenia. It should be offered timely, as soon as treatment-resistance becomes apparent. Clinicians can use personalized augmentation strategies as part of a comprehensive treatment plan in order to achieve improvements even in patients with a poor response to clozapine alone. However, polypharmacy should be used judiciously, keeping in mind medical morbidity and quality of life.DisclosureI have the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution);

A Legal Right to Clozapine Therapy for Incarcerated Individuals With Treatment-Resistant Schizophrenia.

People with serious mental illnesses increasingly are being treated in jails and prisons, and during incarceration are afforded a constitutional right to medical care. This right pertains to both general medical and mental illnesses and both acute and chronic conditions. However, incarcerated patients with treatment-resistant schizophrenia (TRS) often are not offered clozapine, the only medication for this debilitating illness approved by the U.S. Food and Drug Administration. In this column, the authors argue that incarcerated individuals with TRS have a statutory and constitutional right to treatment with clozapine.

An Open-Label, Head to Head Comparison Study between Prucalopride and Lactulose for Clozapine Induced Constipation in Patients with Treatment Resistant Schizophrenia.

Clozapine remains as the gold standard for the management of treatment resistant schizophrenia. Nevertheless, mortality and morbidity associated with Clozapine is partly contributed by its adverse effect of constipation in view of its prominent anticholinergic properties. Despite the evidence that approximately 60% of patients on Clozapine will experience constipation, there is no proper guideline as to the best laxative in the treatment of Clozapine induced constipation. Hence this study was conducted to evaluate the efficacy and safety of Prucalopride and Lactulose in the treatment of Clozapine induced constipation. This was a four week, prospective, open-label head to head comparison study between Prucalopride and Lactulose in the treatment of Clozapine induced constipation. Male and female patients on Clozapine between the age of 18–60 with an established diagnosis of treatment resistant schizophrenia with ≤2 spontaneous complete bowel movement per week were recruited in this study. Eligible patients were assigned into two groups. Patients received Prucalopride 2 mg once daily or Lactulose 10 g once daily for four weeks. Efficacy was analyzed in 58 patients. The proportion of patient with ≥3 spontaneous complete bowel movement (SCBM) was higher in the Prucalopride 2 mg group, reaching significance at Week 4 with p-value of (p = 0.029). The proportion of patient with ≥3 SCBM at Week 1 was 71.4% in the Prucalopride 2 mg group and 60% in the Lactulose 10 g group. The proportion of patient with ≥3 SCBM at Week 4 was 85.7% in the Prucalopride 2 mg group and the proportion remained at 60% in the Lactulose 10 g group. The improvement in the dissatisfaction and treatment satisfaction subscales of the patient assessment of constipation—quality of life (PAC-QOL) were higher in the Prucalopride 2 mg group compared to the Lactulose 10 g group. The common adverse events associated with Prucalopride 2 mg were abdominal pain and loose stools which was transient and subsided within a few days. Over four weeks, in this population of patients with Clozapine induced constipation, Prucalopride 2 mg significantly improved the bowel movement and it was safe.

Nocturnal Enuresis is an Under-recognised Side Effect of Clozapine: Results of a Systematic Review

Objectives Clozapine is an effective antipsychotic medication licenced for the management of treatment resistant schizophrenia. Due to its non-selective pharmacology, it has a broad range of side effects. Nocturnal enuresis secondary to the use of clozapine has been documented in the literature but may be overlooked, the link between drug and symptom being clinically unnoticed. Patients may not mention urinary symptoms due to supervening psychosis, co-existing symptomatology, embarrassment or shame. By raising awareness of the phenomenon, early recognition and patient support may improve compliance with clozapine medication, and consecutively, overall mental health. Consequently, this systematic review investigates the prevalence of nocturnal enuresis secondary to clozapine use. Methods A literature search on clozapine and nocturnal enuresis was used to identify the relevant papers. Papers providing the prevalence data on Clozapine associated nocturnal enuresis were selected for data extraction. Results 47 papers were initially identified. Eight papers focused on the prevalence of clozapine associated nocturnal enuresis (CANE). Point prevalence (nocturnal enuresis at the time of assessment), 1-month prevalence and episode prevalence (nocturnal enuresis since beginning of clozapine) were given. Papers included patients with schizophrenia, schizoaffective disorder, bipolar affective disorder and psychotic depression, taking clozapine medication. The prevalence of CANE ranged from 10–42%. Point prevalence was 21–27%, 1-month prevalence was 10–39% and episode prevalence was 15–42%. Clozapine was more likely to cause nocturnal enuresis compared to other psychotropic medication. Conclusion The prevalence of CANE may be greater than previously thought. However, in order to determine an accurate prevalence of clozapine associated nocturnal enuresis, larger studies with strict inclusion criteria, common definition of diagnosis and prevalence are required. By establishing an accurate prevalence, physician awareness can be improved, and patients can becounselled on the risk of developing the side effect, thus improving early identification and reducing discontinuation rates.

Clinical Guidance on the Identification and Management of Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) occurs in approximately 30% of individuals diagnosed with schizophrenia. The identification and management of TRS in clinical practice are inconsistent and not evidence based. No established clinically relevant criteria for defining and treating TRS exist, although guidelines have been promulgated for clozapine use among TRS patients. This report summarizes the consensus from a roundtable that focused on defining and identifying TRS, pathways to treatment resistance, current treatments, unmet needs, and disease burden. Nine clinical experts in schizophrenia and TRS participated in a closed meeting on June 23, 2017, sponsored by Lundbeck, at which published literature in key areas of TRS research was reviewed. The findings from published studies were synthesized by experts in each area and presented to the group for review and discussion. It was agreed that inadequate response to 2 different antipsychotics, each taken with adequate dose and duration, is required to establish TRS. This recommendation is consistent with guidelines for clozapine use. For each trial, objective symptom measures should be used to assess treatment response, with medication adherence ensured. Once nonresponse is established (after ≥ 12 weeks for positive symptoms [2 trials of ≥ 6 weeks]), the treatment plan should be reevaluated and alternative pharmacologic or nonpharmacologic treatments considered. With increased awareness, those involved in the care of patients with schizophrenia will be able to identify TRS earlier in its course, thus supporting more informed treatment decisions by clinicians, patients, and caregivers to reduce the overall disease burden.

Nocturnal Enuresis is an Under-recognised Side Effect of Clozapine: Results of a Systematic Review

Abstract Objectives Clozapine is an effective antipsychotic medication licenced for the management of treatment resistant schizophrenia. Due to its non-selective pharmacology, it has a broad range of side effects. Nocturnal enuresis secondary to the use of clozapine has been documented in the literature but may be overlooked, the link between drug and symptom being clinically unnoticed. Patients may not mention urinary symptoms due to supervening psychosis, co-existing symptomatology, embarrassment or shame. By raising awareness of the phenomenon, early recognition and patient support may improve compliance with clozapine medication, and consecutively, overall mental health. Consequently, this systematic review investigates the prevalence of nocturnal enuresis secondary to clozapine use. Methods A literature search on clozapine and nocturnal enuresis was used to identify the relevant papers. Papers providing the prevalence data on Clozapine associated nocturnal enuresis were selected for data extraction. Results 47 papers were initially identified. Eight papers focused on the prevalence of clozapine associated nocturnal enuresis (CANE). Point prevalence (nocturnal enuresis at the time of assessment), 1-month prevalence and episode prevalence (nocturnal enuresis since beginning of clozapine) were given. Papers included patients with schizophrenia, schizoaffective disorder, bipolar affective disorder and psychotic depression, taking clozapine medication. The prevalence of CANE ranged from 10–42%. Point prevalence was 21–27%, 1-month prevalence was 10–39% and episode prevalence was 15–42%. Clozapine was more likely to cause nocturnal enuresis compared to other psychotropic medication. Conclusion The prevalence of CANE may be greater than previously thought. However, in order to determine an accurate prevalence of clozapine associated nocturnal enuresis, larger studies with strict inclusion criteria, common definition of diagnosis and prevalence are required. By establishing an accurate prevalence, physician awareness can be improved, and patients can becounselled on the risk of developing the side effect, thus improving early identification and reducing discontinuation rates.

F3. A CASE OF LEUKOCYTOSIS ASSOCIATED WITH CLOZAPINE TREATMENT FOR THE MANAGEMENT OF CHRONIC SCHIZOPHRENIA

BackgroundClozapine is an atypical antipsychotic drug with therapeutic efficacy through serotonin-dopamine antagonism. It has been used for the management of treatment-resistant schizophrenia and reducing the risk of suicidal behavior. In addition to agranulocytosis and leukopenia, clozapine has also been reported to be associated with other types of blood dyscrasias, including leukocytosis.We wish to report a case of leukocytosis associated with clozapine treatment in a patient of chronic schizophrenia.MethodsOur patient is a 48-year-old woman with a diagnosis of schizophrenia since the age of 22. She has a history of numerous hospitalizations and substantial treatment with conservative antipsychotics.We evaluated her medical and psychiatric history as well as mental status. Then We assumed that she might have treatment-resistant schizophrenia and accordingly commenced treatment with clozapine. At the time of admission, her WBC count was 8.01 × 109/L and ANC was 5110. Clozapine was started at 3rd hospital day. We stopped aripiprazole and gradually increased clozapine. Only 2mg of lorazepam was used in combination with clozapine. Remission was achieved with 450 mg/day of clozapine. WBC on the 1st day of treatment was 12.41 × 109/L (ANC; 9481) and clozapine was 300mg/day. WBC on the 18th day of treatment was 15.32 × 109/L (ANC; 12501), and at that time, her clozapine dosage was 450mg/day. At this point, her vital sign was within normal range and physical examination did not showed any infectious signs. On the 25th day of treatment, WBC count was 22.1 × 109/L and ANC was 17680. However, no general medical condition to explain the leukocytosis was found.We concluded that her leukocytosis was linked to clozapine, and decided to taper out clozapine despite there being no medical contraindication. After two weeks from starting blonanserin and olanzapine, WBC count normalized. Fortunately, despite replacing the medication, the remission was maintained.ResultsIn our case, the increase in white blood cell count with increasing dose of clozapine was evident and did not reveal any other medical cause to explain leukocytosis in the patient. In addition, leukocytosis improved significantly after discontinuing clozapine. Also, there have been reports of cases of leukocytosis associated with clozapine treatment, and the mechanism of leukocytosis has been explained to some extent. Considering these temporal associations, mechanisms, and previous cases, it is reasonable to consider leukocytosis associated with clozapine in this case.DiscussionThis case suggests a temporal relationship between the use of clozapine and leukocytosis. It also shows the rapid resolution of leukocytosis after discontinuation of clozapine. The mechanisms of clozapine-induced leukocytosis may be related to changes in plasmatic concentrations of granulocyte colony-stimulating factor, tumor necrosis factor-α, interleukin (IL)-2 and IL-6 cytokines, which could be stimulated by clozapine. In our case, an increase in WBC count was consistent with an increase in clozapine dose, suggesting a dose-dependent effect. However, the appearance of leukocytosis during clozapine treatment does not mean that clozapine should be discontinued. Nevertheless, the WBC continued to increase steadily, and clinicians inevitably replaced the drugs in consideration of the fact that he was not a general hospital but a psychiatric clinic.In this paper we have reported a patient of chronic schizophrenia who developed leukocytosis during clozapine treatment. It appears that most of clozapine-associated leukocytosis can be benign medical condition. However, clinicians should be aware of the dangers of other blood disorders such as leukocytosis.