Management Of Treatment-resistant Schizophrenia Research Articles

Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring.

Concerns exist that clozapine is underutilized in the management of treatment-resistant schizophrenia. Although a 2015 change in the US Food and Drug Administration (FDA) monitoring recommendations lowered the threshold of the absolute neutrophil count for treatment interruption from 1,500/μL to 1,000/μL and removed white blood cell count thresholds from the monitoring algorithm, the implications of this policy change on clozapine interruptions remain unknown. We analyzed outpatient prescribing records for antipsychotic medications in the Veterans Integrated Service Network 7 (VISN 7) database between 1999 and 2012 to assess the potential impact of the recent changes in FDA neutropenia monitoring recommendations on clozapine treatment discontinuation. We evaluated results of complete blood count monitoring to compare percentages of patients who developed or would have developed ≥ 1 hematologic event under the previous and current FDA guidelines in the first year following initiation of clozapine. From a cohort of 14,620 patients with schizophrenia (ICD-9-295.x), 246 patients received clozapine treatment (1.7%). No agranulocytosis was observed during the study period. Under the former recommendations, 5 patients in the clozapine initiation cohort (n = 160, 3.1%; 95% CI, 0.43-5.83) qualified for treatment interruption during the first year of clozapine treatment, while only 1 patient (0.6%) qualified under the current recommendations. Under the former recommendations, hematologic events occurred at a similar rate for individuals taking and not taking clozapine. While clozapine remains an underused medication, the new FDA monitoring guidelines are likely to substantially reduce the percentage of patients who meet criteria for clozapine-associated hematologic events requiring treatment interruption. This decrease may reduce the clinical burden of managing patients on clozapine and therefore increase the number of individuals treated with this uniquely effective medication. However, prospective studies of individuals treated under the new guidelines are needed to fully assess safety of the FDA's change.

SU114. Switching to Clozapine Treatment in Patients With Schizophrenia: The Clinical Course, Remission, and Augmentation of Treatment After the Switch

Background: This study aims to compare clinical features of schizophrenia patients before and after clozapine initiation and to investigate the clinical course of illness, clinical features, remission state, and augmentation methods under clozapine treatment. Methods: A total of 122 consecutive outpatients diagnosed with DSM-IV criteria for schizophrenia and receiving clozapine treatment were included. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Positive and Negative Syndrome Scale, Clinical Global Impression Scale, Global Assessment of Functioning, Calgary Depression Scale for Schizophrenia, Panic Agoraphobia Scale, Yale-Brown Obsessive Compulsive Scale, and the World Health Organization Disability Assessment Schedule-2.0 to determine the severity of psychopathology and comorbid symptoms, as well as the level of functioning and disability. The remission state of the patients was assessed utilizing the Schizophrenia Working Group’s remission criteria for schizophrenia. Results: The number of psychotic relapses, hospitalizations, and suicide attempts along with alcohol-drug misuse rates declined after the initiation of clozapine. The study group consisted of schizophrenia patients using clozapine for a mean period of 9 years, and 44.5% of these patients were found to be in a symptomatic remission state. No relationship was shown between remission state and clozapine dose/plasma levels. Education level was found to be higher, work status better, and comorbid symptom severity lower in remitted patients. There was no difference between remitted and not remitted patients in terms of the duration of clozapine use and age at disease onset. Education level, positive and negative symptom severity predicted achievement of remission on clozapine. The augmentation strategies were examined in patients showing partial response to clozapine, and combined antipsychotic drug use was found to be the most prevalent method utilized. Patients on augmentation treatment were on higher daily clozapine doses and their remission rates were lower. In addition, the severity of psychopathology related with schizophrenia and comorbid symptoms, the level of functioning and disability were worse in this particular patient group. History of antipsychotic combination use prior to clozapine was found to predict the future use of clozapine augmentation. Conclusion: Shortening the duration of switch to clozapine and avoiding antipsychotic combinations prior to clozapine use should both be considered as important goals in the management of treatment resistant schizophrenia.

A review of the safety of clozapine during pregnancy and lactation.

Clozapine is an antipsychotic used in the management of treatment-resistant schizophrenia. However, little is known about clozapine use during pregnancy and lactation, or its impact on the mother, foetus, and infant. This review aims to summarize the available literature on the safety of clozapine use during the perinatal period. EMBASE, PsycINFO, and MEDLINE were searched from their inceptions through June 2016. The review encompasses 21 studies that have examined clozapine use during pregnancy and lactation. The limited available data do not support an increased risk of congenital malformations in foetuses exposed to clozapine during pregnancy, though rates of gestational diabetes are twice as high in pregnant women using clozapine. Clozapine accumulation in foetal serum possibly contributes to increased rates of floppy infant syndrome at delivery, decreased foetal heart rate variability, and seizures in infancy. Clozapine crosses the placenta and also accumulates in breast milk, which may increase the risk of agranulocytosis in infants and may necessitate infant testing. The majority of these data come from case reports and case series, making it unclear if the published risks associated with clozapine are due to mental illness, lifestyle factors, or co-treatment with other psychotropic medications. While the available literature on clozapine use during the perinatal period is very limited, the risks of clozapine use during pregnancy and the postpartum period should be discussed with women and weighed against those associated with other treatments and partially or untreated schizophrenia.

Reasons for discontinuing clozapine: A cohort study of patients commencing treatment

BackgroundClozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries a poor prognosis. MethodsWe investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation. ResultsA total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR=2.12, 95% CI 1.30–3.47). ConclusionsLiving in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment.

Clozapine-induced Gastrointestinal Hypomotility — New Objective Evidence for an Underestimated Side-effect

Clozapine-induced Gastrointestinal Hypomotility — New Objective Evidence for an Underestimated Side-effect

Management of treatment resistant schizophrenia in medium secure care

Thirty-one percent of patients within a male medium secure unit (MMSU) were identified with treatment resistant schizophrenia. Almost half of these patients had not received clozapine treatment at least once during the course of their treatment history. The authors recommend that early identification of these patients and the appropriate use of therapeutic treatments, including clozapine, could lead to better outcomes for patients and significant cost savings for the NHS.

Clozapine response and pre-treatment EEG-is there some kind of relationship.

Background:Clozapine has been used widely in the management of treatment-resistant schizophrenia. The present study aims at determining whether pre-treatment electroencephalography (EEG) abnormalities would serve as a marker for response to clozapine treatment.Subjects and Methods:This was a cross-sectional study done in a tertiary care center in Mumbai where patients diagnosed with schizophrenia using DSM-IV criteria and resistant schizophrenia using Kane criteria were assessed using EEG prior to starting clozapine treatment. They were rated for symptomatic improvement using the Positive and Negative Syndrome Scale (PANSS) along with Clinical Global Improvement for Severity (CGI-S). The results were statistically analysed and presented.Results:55 out of the 80 patients in the study showed baseline EEG abnormalities. The mean duration of illness in the patients were 2.65 years. Slow wave and background EEG abnormalities were common in pre-treatment EEG. 36.4% patients in the study showed clinical response. Patients with negative symptoms and baseline EEG abnormalities showed better response.Conclusions:The study was circumscribed and had many limitations due to a small sample size. The relation between pre-treatment EEG abnormalities and clozapine response could not be statistically correlated and it could not be ascertained to be a marker for response to clozapine therapy.

Exploring the Potential Effect of Polypharmacy on the Hematologic Profiles of Clozapine Patients

Clozapine, an atypical antipsychotic with documented efficacy in the management of treatment-resistant schizophrenia, is associated with the risk of adverse hematological outcomes. Of particular concern are reductions in white blood cells (WBC) and absolute neutrophil counts (ANC). Individuals who display moderate leukopenia (3000/mm(3) > WBC ≥ 2000/mm) upon initiation of clozapine therapy are at increased risk of developing agranulocytosis, defined as an ANC less than 500/mm. Complications of agranulocytosis can be severe and include increased risk of infection and mortality. The primary objective of this study was to examine data on clozapine recipients who experienced adverse drug reactions (ADRs) related to decreases in WBC or ANC and ascertain whether other drugs and/or drug interactions had played a role. The analysis included multiple classes of medications. A retrospective chart review was performed of open and closed medical records of all inpatient recipients of clozapine at a state psychiatric center between January 1, 2004 and June 30, 2011. Laboratory records of patients prescribed clozapine were examined for abnormal WBC counts or ANC. A hematological ADR was considered to have occurred if there was a substantial drop in either WBC or ANC or mild or moderate leukopenia or granulocytopenia. Each episode was analyzed for medications that might have contributed to the ADR. Data were collected for all scheduled and STAT medications started at any point during the clozapine patient's hospitalization. The following seven medication groups, based on the Therapeutic Classification System of the American Hospital Formulary System (AHFS), were chosen for analysis because they were consistently used in the majority of the patient population: antihistamines, anti-infectives, autonomic agents, cardiovascular agents, antipsychotics, vitamins, and gastrointestinal agents. Pearson correlation coefficients were calculated to identify associations between the presence of hematological ADRs and medications administered concomitantly with clozapine. The following significant correlation coefficients were found between the use of a class of medications and the occurrence of a hematological ADR: antiinfective agents 0.409 (p < 0.01), gastrointestinal agents 0.329 (p < 0.01), and autonomic agents 0.309 (p < 0.01). In the subset of patients who were prescribed a proton-pump inhibitor or ranitidine concomitantly with clozapine, 24/26 (96%) experienced a hematological ADR. Autonomic agents, anti-infective agents, and proton pump inhibitors and other gastrointestinal agents were all associated with hematological ADRs when co-prescribed with clozapine. Medications from these classes should be initiated cautiously in patients being treated with clozapine to avoid precipitous drops in ANC or WBC that may increase the risk of agranulocytosis.

Discontinuation of clozapine: a 15‐year naturalistic retrospective study of 320 patients

Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting. Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed. Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms. In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine.

Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital

Clozapine is used in the management of treatment-resistant schizophrenia and is effective in reducing aggression; however a subgroup of patients is poorly responsive. For violent patients in this group, there is limited literature on the use of strategies to augment clozapine with other agents. Here we present a case series of 6 schizophrenia patients, within a high-security hospital, who have a history of serious violence and who were treated with clozapine augmented with amisulpride. We reviewed case notes and health records for evidence of violence/aggression and positive factors such as engagement in activities, and Clinical Global Impression (CGI) scores were formulated. We also examined metabolic parameters before and after augmentation. All 6 of the patients showed clinical improvement in symptoms and a reduction in their risk of violence to others. Five patients had a reduction in number of violent/aggressive incidents, and all patients showed improvement in engagement in occupational, vocational, and/or psychological work. Metabolic parameters were largely unchanged except for 1 patient whose Body Mass Index (BMI) increased. Five patients reported side effects as unchanged or improved. These schizophrenia patients with a history of violence showed clinical improvement and reduced aggression and violence with amisulpride augmentation of clozapine. To our knowledge, this is the first report of an antiaggressive benefit of this combination in forensic psychiatric patients. Further studies are warranted to establish the efficacy and anti-aggressive effects of amisulpride augmentation of clozapine.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance

These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A–F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.

Current perspectives in the treatment of resistant schizophrenia

This article summarizes the current knowledge base on the diagnosis and management of treatment resistant schizophrenia. While the prevalence of treatment resistant schizophrenia is definition dependent, estimates have ranged from 30% to up to 60%. This article first looks into the various diagnostic criteria of treatment resistant schizophrenia. Then the literature is reviewed about the pharmacotherapeutics of its management. Clozapine emerges to be the gold standard. In addition risperidone and high dose olanzapine also emerge as clinically useful options. Other emerging adjunctive treatment options are equally addressed.

Maintenance electroconvulsive therapy (ECT) for treatment-resistant disorganized schizophrenia

Patients who have not responded to recommended antipsychotic medications should be considered for electroconvulsive therapy (ECT). However, there has been controversy about the standardized methods of continuation and maintenance ECT in the management of treatment-resistant schizophrenia. We describe a patient with a serious case of disorganized schizophrenia who had not responded well with any typical and atypical antipsychotic drug for seven years, but responded remarkably to acute ECT. Continuation ECT was necessary to sustain a positive therapeutic response. The patient showed dramatic improvement from 70 to 20 in the 18-item Brief Psychiatric Rating Scale (BPRS) score (71% reduction) after acute ECT and continuation ECT. Using maintenance ECT, she was able to live in the custody of her parents after 7-years hospitalization. This case report suggests that continuation and maintenance ECT benefits patients with serious cases of refractory schizophrenia.

Is clozapine—aripiprazole combination a useful regime in the management of treatment-resistant schizophrenia?

Around 40-70% patients with treatment-resistant schizophrenia fail to respond to clozapine. Though combining antipsychotics is commonly practised with non-responders, there is little evidence for its use.We carried out a retrospective review of case notes of patients with treatment-resistant schizophrenia on clozapine-aripiprazole combination at our clozapine clinic. We report changes in psychotic symptoms, social function, weight, total cholesterol, serum glucose, HDL, CGI and GAF score pre- and post-aripiprazole augmentation. Clozapine-aripiprazole combination was associated with 22% reduction of clozapine dose. Eighteen out of 24 (75%) lost a mean weight of 5.05 kg. There was improvement in positive and negative symptoms, social functions, weight loss and a moderate increase in HDL. Our findings suggest that clozapine-aripiprazole is a safe and tolerable combination; however, control trials are needed to validate our findings.

Management of treatment resistant schizophrenia

Whilst gains have been made in recent years in the pharmacological treatment of schizophrenia, a number of patients still have residual symptoms and disabilities, or simply do not show response to antipsychotic medications. For such 'treatment resistant' patients, there is little by way of randomised controlled data to support any particular type of further intervention, but combinations of agents (combined antipsychotics, augmentation with mood stabilisers, antidepressants, and other agents)can show benefit in certain patients in certain domains of symptomatology and psychosocial functioning. Certain psychological and psychosocial treatment strategies can also be of benefit in this regard. This article selectively reviews the literature treatment resistance in schizophrenia, and emphasises the importance of an holistic approach to individual patients. Keywords : schizophrenia, treatment resistance, antipsychotics, augmentation, psychosocial treatments South African Psychiatry Review Vol. 9(1) 2006: 17-23

A Clinical Monitoring System for Clozapine

To describe a framework for the initiation and ongoing monitoring of patients on clozapine, and detail support materials that can be used in clinical settings, including general practice, to support this process. A framework is described. Clozapine has a special place in the management of treatment-resistant schizophrenia. However, it has certain side-effects that require its use to be carefully evaluated on an individual patient basis, and encompass excellent documentation and discussion with all relevant parties. Comprehensive longitudinal monitoring is required.

Combination of “atypical” antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder

Background: This article reviews the published clinical data on treatment-resistant schizophrenic and schizoaffective patients managed with combinations of “atypical” antipsychotic medication. Method: A computerized MEDLINE literature search covering an 18-year period (1985–2003) was conducted. All pertinent papers on the subject of the use of combination “atypical” antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder were obtained with subsequent analysis and discussion of the retrieved data. Results: The search identified 29 case reports and case series reports (172 patients) and one double-blind placebo-controlled trial (28 patients) describing the use of combination “atypical” antipsychotic medication (clozapine–risperidone; clozapine–sulpiride; clozapine–olanzapine; clozapine–quetiapine; olanzapine–sulpiride; olanzapine–quetiapine; risperidone–olanzapine; risperidone–quetiapine) in the treatment of resistant schizophrenic and schizoaffective patients. An overview of results suggests that the combinations were beneficial in the described patients with reduction of positive symptoms and occasionally negative symptoms. Significant adverse effects, while rare, were reported in a few cases and did not appear to different in nature from those managed on monotherapeutic regimens. Conclusion: Combinations of “atypical” antipsychotic medications are well tolerated and may be effective in the management of treatment refractory schizophrenia and schizoaffective disorder. However, further double-blind placebo-controlled trials are required in order to test and confirm these observations.

Case reports of the reemergence of psychotic symptoms after conversion from brand-name clozapine to a generic formulation

Background: The use of generic drugs has resulted in considerable cost savings; however, whether all generics are truly bioequivalent to their brand-name counterparts is questionable. Although the efficacy of clozapine in the management of treatment-resistant schizophrenia has been well established, reports of relapse after conversion to a generic formulation are becoming more common. Objective: This article presents 7 case studies of patients in a long-term residential care facility who experienced a relapse of psychotic symptoms when the pharmacy inadvertently switched their therapy from brand-name clozapine to a generic formulation. Neither patients, physicians, nor staff of the facility were aware of this switch. Possible reasons for the apparent increased risk of relapse in some patients switched to the generic formulation of clozapine are explored, with reference to US Food and Drug Administration bioequivalence standards and reports. Results: All 7 patients, whose condition had been well stabilized with brand-name clozapine, experienced a rapid and profound deterioration after the switch to the generic formulation. Five patients required hospitalization. All patients responded well when brand-name clozapine was reinstated. Conclusion: The findings suggest that brand-name clozapine and the generic formulation may display important clinical differences, and a comparable therapeutic response may not be achievable despite adequate monitoring. Large, controlled, prospective trials are needed to clarify the potential for treatment failure with the use of generic clozapine.

A randomized controlled trial of cognitive behaviour therapy in the management of treatment-resistant schizophrenia

A randomized controlled trial of cognitive behaviour therapy in the management of treatment-resistant schizophrenia

The Cost-Effectiveness of Clozapine

Treatment-resistant schizophrenia is a severely debilitating and costly disease. While clozapine is reported to be an effective therapy for treatment-resistant schizophrenia, it is nevertheless largely underutilised. A review of published cost-effectiveness studies of clozapine conducted in the USA, UK, Sweden and Canada, and employing a variety of study designs, reveals consistent reporting of clinical efficacy, cost and cost-effectiveness findings in favour of clozapine over conventional antipsychotics in the management of treatment-resistant schizophrenia. All reported economic evidence indicates that, despite its higher acquisition cost, clozapine nevertheless represents cost-effective therapy for treatment-resistant schizophrenia. Furthermore, the evidence indicates that, for many patients, clozapine may substantially reduce costs associated with treatment-resistant schizophrenia.