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Reasons for clozapine discontinuation in patients with treatment-resistant schizophrenia
Abstract
Although clozapine is more effective than other antipsychotics in the treatment of schizophrenia, the rate of its discontinuation is also high. The aim of this retrospective chart-review study was to investigate the causes of clozapine discontinuation in patients with treatment-resistant schizophrenia. This study included a total of 396 patients with schizophrenia, 240 still on clozapine therapy and 156 who discontinued clozapine, and compared their clinical characteristics. Those who discontinued clozapine had a longer history of illness and more hospitalizations before clozapine and tended to be older. Inadequate response was more common among clozapine discontinuers compared to continuers. The most common reason for discontinuation was the side-effects associated with clozapine (49%). Discontinuation from patient decision or by the psychiatrist due to noncompliance was the second (29.7%) and discontinuation due to lack of efficacy was the third most frequent reason (21.3%). The patients who discontinued clozapine because of cardiac side effects were younger, had shorter duration of clozapine use, and had lower maximum clozapine dose compared to the other discontinuers. Our findings point out the importance of enhancing psychiatrists’ ability to handle manageable side effects to minimize discontinuations and maximize the benefits of clozapine in patients with treatment-resistant schizophrenia.
... Compared to those who kept on taking clozapine, those who discontinued clozapine had a longer duration of illness, a higher number of hospitalizations, and were older. [13] The most common reasons for discontinuation were side effects (49%), noncompliance (29.7%), and lack of ef icacy (21.3%). [13] A study from the USA showed that more than half (n = 183/320, 57%) of the patients on clozapine had at least one discontinuation at a median of 609 days. ...
... [13] The most common reasons for discontinuation were side effects (49%), noncompliance (29.7%), and lack of ef icacy (21.3%). [13] A study from the USA showed that more than half (n = 183/320, 57%) of the patients on clozapine had at least one discontinuation at a median of 609 days. The most common reasons for discontinuation were nonadherence (35%) and side effects (28%). ...
... The studies from developed countries which have evaluated the factors associated with clozapine discontinuation have been inconsistent. They have reported clozapine discontinuation to be associated with side effects, noncompliance, [13,14] lack of ef icacy, [13] African American race, higher age at the time of starting clozapine, and lower level of improvement in psychiatric symptoms. [14] When we compare the reasons for dropout with these indings, it is evident that a signi icant proportion of patients report a lack of bene its and the side effects of treatment as the reasons for dropping out of the treatment and support the western literature. ...
Background and aim:
The present study aimed to assess the treatment dropout rates, reasons for treatment dropout, and clozapine discontinuation rate among patients attending a tertiary care center in North India.
Materials and methods:
Clozapine data bank was used to identify patients on clozapine, and their treatment records were reviewed for the period Jan 2020-March 2020. Patients who did not follow-up at least once in the last 6 months were considered to have dropped out and were contacted telephonically to understand the reasons for dropout. Treatment records of those following up regularly were reviewed to check if clozapine was discontinued and if so, the reason for the same was evaluated.
Results:
Out of 671 patients on clozapine, 495 (73.8%) were still on regular follow-up and the remaining 176 (26.2%) had dropped out of treatment. Out of the 176 patients who had dropped out of treatment, 84 could be contacted. Common reasons for dropout were long distance from the hospital (n = 27), long waiting time for consultation (n = 8), no benefit with treatment (n = 17), side effects with medication (n = 10), moving away to another place (n = 6), refusal by the patient to follow-up (n = 7), patient improved and so did not feel the need to continue treatment (n = 7), and other reasons (n = 37).
Conclusion:
About one-fourth of patients who had started treatment with clozapine dropped out from the treatment. The most common reasons for dropout from treatment included long distance from the hospital and no benefit from treatment.
... 8 However, interruptions and discontinuation of clozapine treatment are common in clinical practice, and various authors have reported rates ranging from 20% to 60%. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Older age, African-American and African-Caribbean background, substance abuse, living in deprived areas, and male sex were found to be associated with clozapine discontinuation by some researchers. 10,11,13,14,[16][17][18] Most research on the rates and reasons for cessation of clozapine treatment have been reported from the United States and Europe, with limited contributions from the Asian regions. ...
... The reported discontinuation rates due to adverse effects have varied significantly between studies, ranging from 5% to more than 50%. 15,16,19 Among adverse effects, hematological and neurological ones such as neutropenia, agranulocytosis, seizures, and sedation were the most frequently reported reasons encompassing up to 75% to 80% of discontinuation due to adverse effects. 10,14,19 Remarkably, from Australia, significantly higher rates of clozapine-associated myocarditis and cardiomyopathy have been reported compared with international figures. ...
... 15,16,19 Among adverse effects, hematological and neurological ones such as neutropenia, agranulocytosis, seizures, and sedation were the most frequently reported reasons encompassing up to 75% to 80% of discontinuation due to adverse effects. 10,14,19 Remarkably, from Australia, significantly higher rates of clozapine-associated myocarditis and cardiomyopathy have been reported compared with international figures. 26,27 Hence, it is possible that the nature of adverse effects leading to interruptions of clozapine treatment could be different in Australian settings compared with those reported from elsewhere. ...
Background:
Differing rates and reasons for interruptions of clozapine treatment have been reported globally. This article evaluated the rates and reasons for clozapine therapy interruptions in Australia and explored the impact of the frequency of hematological monitoring on these parameters.
Methods:
Data of the patients who were newly commenced on clozapine at three metropolitan public mental health services in Western Australia over 11 years were retrospectively collated. The rate and reasons for clozapine therapy interruptions and their association with the frequency of hematological monitoring, age, sex, and treatment site were analyzed using parametric, nonparametric, and correlational analyses.
Results:
Of the 457 patients whose data were collected, 69.6% had an interruption of treatment with 41.2% of those occurring during the period of mandatory weekly hematological monitoring in the first 18 weeks. Nonadherence (57.4%) and adverse effects (28.8%) were the 2 main reasons for the treatment interruptions. Cardiac issues accounted for the majority of the interruptions (61.8%) due to specified adverse effects, and these occurred significantly more commonly within the first 18 weeks. Location, age, and sex did not predict the possibility of treatment interruptions.
Conclusions:
The high rates of clozapine treatment interruption observed during the period of weekly monitoring point toward the need to address the burden of frequent hematological monitoring for patients. Disproportionately higher rates of interruption due to cardiac adverse effects observed in this study compared with research from non-Australian settings raise the possibility of geographical differences in the adverse effects leading to treatment discontinuation.
... 9,10 Approximately 20% of all patients discontinue clozapine treatment. 6,11 Adverse drug reactions represents 60% of these cases, while nonadherence, the second most common reason for discontinuation, represents 15% to 20% of the events. 6,11 Only approximately 5% of the cases of clozapine discontinuation are caused by insufficient clinical effect. ...
... 6,11 Adverse drug reactions represents 60% of these cases, while nonadherence, the second most common reason for discontinuation, represents 15% to 20% of the events. 6,11 Only approximately 5% of the cases of clozapine discontinuation are caused by insufficient clinical effect. 6,11 There is a substantial risk of symptom relapse and hospitalizations after a failed clozapine trial. ...
... 6,11 Only approximately 5% of the cases of clozapine discontinuation are caused by insufficient clinical effect. 6,11 There is a substantial risk of symptom relapse and hospitalizations after a failed clozapine trial. 4,12 Increased knowledge on mechanisms underlying the tolerability issues of clozapine is therefore necessary. ...
Purpose/background:
Pharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations.
Methods/procedures:
Adult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018-2020. Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last clozapine intake, and (3) detectable levels of N-desmethylclozapine, clozapine-N-oxide, clozapine-5N-glucuronide, or clozapine-N+-glucuronide. Patients comedicated with cytochrome P450 enzyme inducers, inhibitors, or valproic acid were excluded. The high-resolution mass spectrometry assay enabled detection of 21 clozapine metabolites. Metabolite profiles were compared between patients switching treatment (switchers), measured as clozapine being replaced by another antipsychotic drug in blood samples, versus maintaining clozapine treatment (nonswitchers) during the study period.
Findings/results:
Of the 84 patients fulfilling the study criteria, 7 patients (8.3%) were identified as clozapine switchers. After correcting for smoking habits, the clozapine-5N-glucuronide/clozapine ratio was 69% lower (P < 0.001), while the clozapine-N+-glucuronide/clozapine-5N-glucuronide ratio was 143% higher (P = 0.026), respectively, in switchers versus nonswitchers. The other metabolite ratios did not significantly differ between switchers and nonswitchers.
Implications/conclusions:
The present study found a significantly reduced 5N-glucuronidation phenotype in patients switching from clozapine at therapeutic serum concentrations (>1070 nmol/L) to other antipsychotic drugs. This may indicate that glucuronidation, as a potential detoxification mechanism, is related to clozapine tolerability. However, the causality of this observation needs to be investigated in future studies with larger patient populations.
... Is it that people with psychosis are actually unable to improve, or that the system is benefitting from them being sick, maintaining their dependency on antipsychotic medication, case managers, and psychiatric practitioners? A study of 156 patients who discontinued taking their prescribed antipsychotic medication, clozapine, revealed that half did so due to unwanted clozapine side effects, including cardiac problems, low white blood cell count, seizures, and unwanted sedation (Ucok et al. 2019). The solution for psychiatrists that was suggested in the same article was to encourage maintenance of the 'treatment' to prevent 'non-compliance' (Ucok et al. 2019). ...
... A study of 156 patients who discontinued taking their prescribed antipsychotic medication, clozapine, revealed that half did so due to unwanted clozapine side effects, including cardiac problems, low white blood cell count, seizures, and unwanted sedation (Ucok et al. 2019). The solution for psychiatrists that was suggested in the same article was to encourage maintenance of the 'treatment' to prevent 'non-compliance' (Ucok et al. 2019). Clozapine has notoriously adverse side effects but is still being used to treat psychotic symptoms when other antipsychotics are not effective (Correll et al. 2022). ...
The history of the recovery movement began with a pushback against treatment, and the philosophies that it was founded upon still have relevant applications to contemporary social work practice. Financial aspects of service provision for people with serious mental illnesses have enabled other actors in the medical model of psychosis treatment to benefit, while disempowering and dehumanizing the consumers of those services. Since then, other movements like Psychopolitics and the Mad Movement have helped empower psychosis survivors to advocate for their right to self-determination amid the epistemological pressure to identify as disabled. Social workers would like to believe that the field has moved beyond the philosophies that perpetuated institutionalization of people with serious mental illnesses. Contemporary examples, however, reveal how social services in the US maintain the status quo of sanism for psychosis survivors.
... Discontinuing clozapine may be due to a rare but serious side effect such as myocarditis, neutropenia, seizures, or constipation, or due to several persistent and intolerable effects such as sedation or weight gain [2,[5][6][7]. Other factors may mean clozapine is discontinued, for example, if it is ineffective or due to personal beliefs about illness [7][8][9][10][11][12]. There are retrospective case note studies describing the consequences of clozapine discontinuation [4,6], where the risk of relapse is high and the clinical outcome is usually poor [4,5]. ...
... Fear of becoming unwell and recurrence of negative experiences are described by people discontinuing antidepressants [41] as well as antipsychotics [32,35]. Clinicians are advised to identify potential causes of non-adherence and manage side effects [6,12]; there is less emphasis on understanding the patient perspective, enabling people to participate in shared decision making [40,[42][43][44] to minimise non-adherence with clozapine. In the main, discontinuation of any type of medicine is examined in terms of clinical measurements and not patient experience [4,24,45,46], making it an important area of research. ...
Background
Discontinuing what is considered the most effective treatment for treatment-resistant schizophrenia may precipitate feelings of failure or a relapse of illness. Clozapine treatment is discontinued for a variety of reasons, including non-adherence, intolerance, or lack of efficacy. Patients’ experiences of discontinuing the “best” treatment and the impact on perceptions of subsequent antipsychotic treatment are important in developing an understanding of the factors affecting people’s treatment choices. This study is the first of its type, seeking to explore people’s perspectives on clozapine discontinuation.
Method
Semi-structured interviews with sixteen patients who had received clozapine and discontinued treatment—thirteen males and three females, age range: thirty-two to seventy-eight years old—were audio-recorded and transcribed. A modified inductive approach to analysis, based on grounded theory, was taken to identify commonalities and differences in patients’ perceptions.
Results
The three main themes identified from participants’ experiences were:positive and negative effects of treatment;
feelings of agency, being the capacity to make decisions about treatment and act independently;
choice of treatment in the future.
Participants exhibited agency in making choices about medication, including risking relapse, while attempting self-management of medication effects. Different participants perceived the same side effect as beneficial or intolerable. Variation in subsequent treatment choices was reported, with some participants favouring depot (long-acting) injections. A participant was frightened when not told about clozapine’s side effects, which led to the participant not being engaged in future treatment decisions. Others, despite suffering serious adverse effects, retained positive perceptions of clozapine; they experienced despair at finding an effective alternative.
Conclusions
Experiences with clozapine discontinuation evoked powerful emotions and resulted in clozapine being the benchmark for other treatments. Knowledge, agency, and being in control were important to participants in relation to treatment. Personal perceptions of treatments or beliefs about illness could lead to non-adherence. People value the clinician listening to their experiences to better understand their perspective, enabling concerns about medication to be addressed through true shared decision making.
Trial registration
NHS Health Research Authority and Health and Care Research Wales, IRAS Project ID 225753, Research Ethics Committee (REC) reference: 18/NW/0413, 25/06/2018.
... 4,5 The most common reasons for discontinuation are side effects of clozapine, noncompliance, and lack of efficacy. [6][7][8] Discontinuation of clozapine often results in poor outcome 9 or even worse conditions such as a reincreased risk of suicide. 10 Alternative treatment strategies after discontinuation of clozapine are usually not as satisfactory as clozapine treatment. ...
... This may have an additional effect on compliance to clozapine by reducing the side effect burden, as side effects of clozapine are a major cause for discontinuation. 6,7 In addition, Tiihonen et al 25 argued that it is possible for patients to use at least one of the prescribed drugs when they receive prescriptions for 2 antipsychotics in their nationwide cohort study. ...
Background:
Combining clozapine with a long-acting injectable antipsychotic (LAI) or using different, nonstandard formulations of the compound may improve treatment outcomes. We aimed to investigate the utility of the clozapine-LAI combination and different formulations of clozapine for compliance problems of clozapine treatment, and to describe a case series on the combined treatment.
Procedures:
We conducted a PubMed search with no date restriction. The number and length of hospitalizations, the results of clinical scales, and adverse events were recorded. We present 18 patients using the clozapine-LAI combination. Data were collected from the medical charts and electronic records.
Results:
We extracted 9 records describing the use of the clozapine-LAI combination. The case reports and mirror-image studies showed a significant reduction in the number of hospitalizations, length of hospital stays, and number of visits to the emergency department on the combined treatment with no serious adverse events. We included 11 articles for clozapine formulations. The case reports and retrospective data suggested that short-acting intramuscular clozapine was often well tolerated and resulted in an increased acceptance of oral clozapine in the acute phase of illness. In our case series, illness severity and the number of hospitalization per year significantly decreased after the combined treatment, besides a significant improvement in the functioning scores. Hyperprolactinemia and extrapyramidal side effects were reported due to concomitant LAIs.
Conclusions:
Despite the encouraging evidence, the present data are preliminary and mostly based on retrospective studies, and oral-dissolving tablets or oral liquid formulations of clozapine have insufficient evidence for clinical practice. Well-designed, controlled, follow-up studies are needed for both clozapine-LAI combination and different formulations of clozapine.
... [8][9][10][11][12][13][14][15][16][17] Non-adherence and adverse effects were the two most common reasons reported for clozapine discontinuation in these studies. Older age at commencement of clozapine, 9,10,12,15,16 African ethnicity, 8,9,13,16,17 substance abuse, 15 male gender, 18 reduced treatment efficacy 19 and living in a deprived neighbourhood 17 have been reported to be associated with clozapine discontinuation. ...
... Most studies have observed that discontinuation of clozapine occurs early during treatment. 8,10,12,[15][16][17]19 Termination of clozapine can be associated with rebound cholinergic overactivity, intractable psychosis, increased mortality, hospitalization, compulsory treatments, and poorer functioning. 14,[20][21][22][23][24] Evidence for effectiveness of alternate antipsychotics after cessation of clozapine in patients with TRS is lacking and recommencing clozapine could be the safest and most effective intervention in many instances. ...
Objective
The proportion of patients who recommence clozapine after cessation, the time taken to resume clozapine post-cessation, and distinguishing demographic and clinical characteristics of this group have been poorly researched. We evaluated these in the current study.
Method
We retrospectively extracted selected demographic and clinical variables and clozapine treatment interruption and recommencement data up to December 2018 of a cohort of 458 patients who first commenced clozapine between 2006-2016. The study was conducted at three Australian health services.
Results
Of the 310 (69%) patients who had at least one interruption of clozapine treatment, 170 (54.8%) did not resume clozapine and 140 (45.2%) recommenced it after the first interruption. More than half of those who recommenced did so within a month and 80% by 12 months. Cox regression analysis revealed that age was found to be significantly associated with recommencement, with a 2% decrease in the likelihood of restarting after an interruption for each year later that clozapine was initially commenced (HR=0.98 95%CI: 0.97, 0.997, p=0.02). Those who ceased clozapine due to adverse effects were less likely to restart than those who ceased due to noncompliance (HR=0.63 95%CI:0.41, 0.97, p=0.03). More time on clozapine prior to interruption increased the likelihood of restarting it, with each additional month on clozapine increasing this likelihood by 1% (HR=1.01 95%CI:1.01,1.02) p<0.001).
Conclusion
If the distinguishing demographic and clinical characteristics of the group identified in this study are corroborated through further research, this could further validate the need to identify treatment resistance and commence clozapine early in people with schizophrenia and provide appropriate interventions to those more at risk of permanent discontinuation of clozapine.
... Majority of patients in our study were males, unmarried, unemployed, living in nuclear families, and belonging to lower socio economic class. The sociodemographic profile of our study sample is in accordance with studies conducted previously [20][21][22][23]. The most common indication of clozapine in our study is treatment-resistant schizophrenia. ...
... Hypersalivation along with sedation has been found to be one of the two commonest side effects in majority of studies [3,[37][38][39]. Ucok A et al. found sedation in 41.4% patients and reported it to be a reason for poor compliance and discontinuation in patients on clozapine [21]. Twenty six (26%) of the patients in our study complained of dry mouth. ...
Background
Clozapine is an atypical second-generation antipsychotic belonging to the family of dibenzodiazepines. There is lack of literature on clozapine from this part of the world. So, our aim was to study the socio demographic, clinical and side effect profile of patients on clozapine in Kashmir.
Results
The mean age of the study group was 32.6 ± 8.9 years with majority being males (78.4%), unmarried (78.4%), unemployed (77.2%), and belonging to nuclear families (77.2%). Almost half of them resided in urban localities (51.1%) and studied upto middle school (55.7%). Around three- fourth (75%) of the patients had diagnosis of treatment-resistant schizophrenia. The mean dose of clozapine was 338.92 ± 158.11 mgs. Sedation (76.1%), hypersalivation (69.5%), constipation (46.6%), and weight gain (34.1%) were most common side effects noted in patients. 4.5% cases developed seizures while on clozapine. 2.3% patients developed agranulocytosis while 4.5% patients developed neutropenia on clozapine. The neutropenia was more pronounced in patients of schizophrenia with suicidal tendencies with doses of more than 400 mg.
Conclusions
We have used clozapine in a wide range of indications. Our patients seem to tolerate and respond to higher doses of clozapine and the prevalence of blood dyscrasias in our study sample was much higher than the rest of India.
... However, severe adverse effects (AEs) (e.g. myocarditis, agranulocytosis, metabolic syndrome) may limit clozapine use and delay its timely introduction in TRS [9]. Multiple efforts have been made over the years to conceive a drug with similar action and efficacy but without potential AEs. ...
Introduction
Treatment resistant schizophrenia (TRS), the lack of response to at least two antipsychotics administered at adequate dose and duration, epitomizes in psychiatry one of the most difficult-to-treat pathologies, epidemiologically relevant (affecting one third of schizophrenia patients) and with severe consequences for the patients in terms of overall functioning. After 50 years only one drug is approved for TRS: clozapine. Furthermore, a few patients do not respond even to clozapine and are indicated as clozapine-resistant patients.
Areas covered
In this review and expert opinion, we have critically appraised the current literature, discussing the role of old and new agents in treating resistant schizophrenia.
Expert opinion
The search for therapy against TRS, beyond clozapine or in addition to clozapine, has emerged over time, capturing mainly three types of strategies: 1) Add-on of a second-generation antipsychotic (i.e., amisulpride); 2) Add-on of a second antipsychotic with significantly different receptor profile compared to the older ones (e.g., aripiprazole and cariprazine); 3) Novel strategies beyond dopamine D2/D3 receptor occupancy (e.g., xanomeline+trospium, TAAR1-agonists, sodium benzoate, and D-amino acids). More high-quality clinical trials applying the current operationalized criteria for TRS and clozapine-resistance are required to evaluate the efficacy of alternative and add-on treatments.
... Unlike typical first generation antipsychotics that were primarily known as D2 receptor antagonists, atypical second generation antipsychotics affected a range of receptors (dopamine D1, D2, D3 and D4, adrenergic α 1 and α 2 , histaminergic H 1 , muscarinic M 1 , M 3 and M 4 , ionotropic NMDA and metabotropic glutamate, and serotonergic 5-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 6 and 5-HT 7 , with lower propensity to cause EPS than first generation drugs (16,(37)(38)(39)(40). However, while a broad receptor binding profile could enable drug effects on multiple targets for broader symptom efficacy, it is also likely to underlie the numerous adverse side-effects associated with the use of second generation antipsychotic drugs, including metabolic side-effects (16,19,(41)(42)(43)(44). Therefore, while atypical antipsychotics had gained popularity for both approved and off-label prescription (45)(46)(47)(48), the side-effects profile, persistence in symptoms in some individuals and, more recently, the question of whether these drugs were actually better than typical antipsychotics (49), remained important factors. ...
Schizophrenia is a complex disorder of varied etiology, manifesting symptoms that can differ between patients and change throughout an individual's lifespan. Antipsychotic drugs have evolved through first (e.g., haloperidol), second (olanzapine and clozapine) and a possible third (aripiprazole) generation of drugs in an attempt to improve efficacy and tolerability, with minimal side-effects. Despite robust scientific efforts over the past 70 years, there remains a need to develop drugs with greater efficacy, particularly in relation to the negative and cognitive symptoms of schizophrenia, addressing treatment resistance, with a lower side-effects profile compared to existing antipsychotic drugs. Identifying and investigating novel therapeutic targets remains an important component of future antipsychotic drug discovery; however, mounting evidence demonstrates neurobiological, neuroanatomical and functional heterogeneity in cohorts of individuals with schizophrenia. This presents an opportunity to refresh the approach to drug trials to a more targeted strategy. By increasing understanding of the basic science and pharmacological mechanisms underlying the potential antipsychotic efficacy of novel therapeutics prior to clinical trials, new drugs may be appropriately directed to a target population of schizophrenia subjects based on the drug mechanisms and correlating biological sub-groupings of patient characteristics. Improving the lives of sub-populations of people with schizophrenia that share common biological characteristics and are likely to be responsive to a particular compound may be more achievable than aiming to treat the complexities of schizophrenia as a homogenous disorder. This approach to clinical trials in antipsychotic research is discussed in the present review.
... 14,15 In comparison, the prevalence of neutropenia in the general population of Denmark and the United States has been estimated to be about 1%. 16,17 Among the hematological adverse reactions leading to clozapine discontinuation, CAN is the most important contributor, with studies reporting that 4.5-14.2% of all clozapine discontinuations are due to CAN. [18][19][20][21][22] The clinician-based decision to discontinue clozapine treatment due to CAN is a consequence of current European guidelines that mandate discontinuation of clozapine treatment in all patients with CAN in order to prevent fatal outcomes. 23 It has been reported that mild or moderate CAN should not generally warrant clozapine discontinuation, but could be managed with other strategies, for example, bone-marrow-stimulating drugs such as granulocyte colony-stimulating factor, lithium or filgrastim. ...
Introduction
The antipsychotic drug clozapine remains underutilized partly because of the risk of life-threatening adverse effects, such as neutropenia. Therefore, an extensive hematological monitoring program was set up to detect neutropenia.
Methods
In this retrospective cohort study, we used registry-based data from the Capital Region of Denmark to investigate incidence rates of neutropenia among patients with a diagnosis of schizophrenia or other psychotic disorders and treated with clozapine for the first time. In a within-subject design, we compared rates of neutropenia in time periods where patients were exposed to clozapine versus time periods, where they were not exposed to clozapine. We also investigated whether the lengths of clozapine-associated neutropenia (CAN) were related to discontinuation of clozapine treatment.
Results
Data from 520 clozapine users were included. The incidence rate of CAN was 3.2 cases per 100 person-years (95% confidence interval [CI]: 2.1–4.8) throughout the entire study. There was no significant difference in incidence rates of neutropenia during clozapine exposure and non-clozapine exposure, with an incidence rate ratio of 0.7 (95% CI: 0.4–1.3). One episode of severe neutropenia was detected. Episodes of CAN with only one sub-threshold neutrophil count were not associated with higher clozapine discontinuation (26%) than CAN episodes of more than one sub-threshold neutrophil count (28%).
Conclusion
In the present study, we could not confirm that clozapine treatment was associated with neutropenia.
... [3][4][5] There are certain circumstances, however, where it is necessary to stop clozapine with estimates of discontinuation ranging between 16% and 66%. [6][7][8][9][10][11][12][13][14][15] There are several reasons to stop clozapine, however they can be broadly divided into indications leading to either emergency, or elective discontinuation (table 1). Emergency discontinuation of clozapine is typically indicated when patients experience potentially life-threatening adverse effects, such as agranulocytosis, myocarditis, or neuroleptic malignant syndrome. ...
Clozapine is the only antipsychotic that is effective in treatment-resistant schizophrenia. However, in certain clinical situations, such as the emergence of serious adverse effects, it is necessary to discontinue clozapine. Stopping clozapine treatment poses a particular challenge due to the risk of psychotic relapse, as well as the development of withdrawal symptoms. Despite these challenges for the clinician, there is currently no formal guidance on how to safely to discontinue clozapine. We assessed the feasibility of developing evidence-based recommendations for (1) minimizing the risk of withdrawal symptoms, (2) managing withdrawal phenomena, and (3) commencing alternatives treatment when clozapine is discontinued. We then evaluated the recommendations against the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. We produced 19 recommendations. The majority of these recommendation were evidence-based, although the strength of some recommendations was limited by a reliance of studies of medium to low quality. We discuss next steps in the refinement and validation of an evidence-based guideline for stopping clozapine and identify key outstanding questions.
... However, when revealing low concentrations, the patient may have switched from clozapine to other antipsychotic drugs instead. The latter is supported by guidelines recommending that dose should be titrated until therapeutic serum concentrations are reached [31,39,41] and also agrees with a study showing that intolerability during low dosing is the main reason for discontinuing clozapine treatment [49]. Furthermore, a pragmatic point is the range of clinical studies showing that clozapine discontinuation is rarely caused by inadequate efficacy [12,14,50]. ...
Background
Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment.Objective
We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service.Methods
Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005–2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included.ResultsIn total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032).Conclusions
The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.
... Even if the risk of suicide decreases with the introduction of clozapine therapy, it increases again upon its discontinuation (Patchan et al., 2015), and the risks associated with treatment discontinuation are significant. The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders (Ucok et al., 2019). A comprehensive review published in 2013 reported neutropenia/leukopenia, severe constipation, and seizures as manageable adverse events, while agranulocytosis and cardiac disorders lead to rapid discontinuation of clozapine without re-administration (Nielsen et al., 2013). ...
Clozapine is the only effective antipsychotic drug used for the treatment of treatment-resistant schizophrenia. Although it has been shown that the frequency of clozapine use is very low in Japan, our previous study revealed that the number of clozapine prescriptions has been increasing in recent years, and that risk factors leading to discontinuation of clozapine were also identified as age ≥40 years, poor tolerability to olanzapine, previous treatment with clozapine, and white blood cell count <6000/mm3. The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders. In this study, we analyzed the physical details and backgrounds of patients with adverse events that led to clozapine discontinuation using a national registry database of more than 8000 Japanese patients. The physical adverse events that led to discontinuation of clozapine were neutropenia/leukopenia, glucose intolerance, cardiac disorders, gastrointestinal disorders, neuroleptic malignant syndrome, pleurisy, pulmonary embolism, sedation/somnolence, and seizures. Neutropenia/leukopenia had the highest incidence (5.0%). Neutropenia/leukopenia and cardiac disorders tended to occur early in the treatment period, indicating the need for careful monitoring for these adverse events in the early stages of clozapine treatment. Gastrointestinal disorders occurred over a long period of time, suggesting the need for careful observation during the maintenance period. The data obtained in our study will lead to the optimal and safe use of clozapine treatment.
... TRS was defined as no response to treatment with at least two antipsychotics at appropriate doses used for at least 6 weeks (Üçok et al., 2015). TRS status for the majority of the patients has been already analyzed in detail in two study centers for our previous reports (Üçok et al., 2015;Ucok et al., 2019). We also divided the patients based on trajectory of the illness as good (episodic with remission or partial remissions) and poor (continuous with stable or deteriorating) course. ...
The aim of this study was to evaluate discontinuation and hospitalization rates in patients with schizophrenia spectrum disorder who were treated with long-acting injectable (LAI) antipsychotics. We recorded clinical data about the period before the LAI treatment, when LAI treatment was initiated, and during the LAI treatment. Variables related to early (<8 weeks) and other LAI discontinuations and hospitalization were analyzed. Out of 452 patients, 14.4% of them discontinued their LAI treatment before 8 weeks, another 24.8% of the patients stopped their LAI by themselves later. Early discontinuers were younger, had shorter duration of illness, and less educated. Sixty-two (27.2%) of the patients were hospitalized under LAI treatment and 40% of the hospitalizations occurred in initial 6 months. Rate of hospitalization was 36.1% in the group who discontinued LAI after 8 weeks. In logistic regression analysis, younger age, history of combined antipsychotic treatment, number of hospitalizations before LAI, use of LAI for less than 6 months and alcohol abuse under LAI treatment were found related to hospitalization. Our findings suggested that discontinuation and hospitalization are still common among the patients who were treated with LAI antipsychotics.
... To capture the complexity of therapeutic response, we included articles that used clinical, service use and functional measures of clozapine response, whether reported as categorical or continuous outcome variables. All-cause discontinuation of clozapine was not an eligible outcome measure because factors other than lack of efficacy may contribute to cessation of clozapine treatment (Legge et al., 2016;Üçok et al., 2019). The meta-analysis included a subset of articles where clozapine response was defined as symptomatic improvement on clinical rating scales (see Section 'Meta-analysis'). ...
Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [ g = 0.31; 95% confidence interval (CI) 0.06–0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.
... Although less severe, these common AEs affect patients' quality of life and may cause emotional distress, thus undermining compliance to treatment and increasing the risk of psychotic relapses. Indeed, beside the potentially dangerous and difficult-to-tolerate ones, also manageable AEs were reported among the causes of treatment discontinuation, which is reported between 20% and 60%, both due to clinician-led or patient decision (Ucok et al., 2019, Legge et al., 2016. Considering the absence of effective alternative therapeutic strategies, CLZ AEs should be carefully monitored, early detected and managed in order to reduce treatment cessation (De Berardis et al., 2018). ...
Clozapine is the only evidence-based drug indicated for Treatment Resistant Schizophrenia but it is largely underprescribed, partially due to its life-threatening adverse effects (AEs). However, clozapine treatment is burdened by other common AEs as constipation, hypersalivation, postural hypotension, tachycardia and metabolic abnormalities. Few studies have investigated sex-related differences in clozapine's tolerability, reporting women to experience more frequently weight gain, hyperglycemia and constipation, while men hypertension and dyslipidemia. Based on these premises, we investigated clinical, psychopathological and metabolic sex-related differences among 147 treatment-resistant patients treated with clozapine, with a specific focus on non-life-threatening AEs. We observed significant higher prevalence of tachycardia in men, and of orthostatic hypotension and constipation in women. Concerning metabolic alterations, we observed significant lower levels of HDL-cholesterol and higher prevalence of hypertriglyceridemia among men, whereas females showed higher prevalence of abdominal obesity. Consistently with previous studies, our data confirm the presence of sex-related differences in clozapine tolerability, with a main effect of sex especially for tachycardia, postural hypotension and constipation. Although non-life-threatening, these common AEs significantly affect patients’ quality of life, undermine compliance and cause treatment discontinuation. A better understanding of this topic could contribute to tailor therapeutic approaches, thus improving tolerability, compliance and clinical stability.
... VE. The observational studies have reported that patients who were prescribed with clozapine are at risk of developing myocarditis and sudden cardiac death [12]. Our patient experienced VE within 6 weeks of clozapine therapy. ...
Background
Clozapine is one of the most efficacious antipsychotic drug used for the treatment-resistant schizophrenia; it is sometimes associated with serious adverse reactions like agranulocytosis, myocarditis, cardiac rhythm disturbances, etc.
Case presentation
A 30-year-old patient with a primary diagnosis of paranoid schizophrenia (ICD code - F20.05) was on regular prescription for 6 years. Due to refractoriness, the patient was initiated on tablet clozapine. After 45 days of clozapine therapy, he presented with the complaints of worsening of positive symptoms and sudden falls associated with a brief period of unresponsiveness for which the patient was admitted for evaluation. After stabilization of the patient, it was concluded that he was suffering from ventricular ectopics based upon cardiac investigations like electrocardiogram (ECG) and Holter monitoring. Upon causality assessment between the adverse drug reaction (ADR) and the suspected drug using Naranjo Scale and WHO causality assessment scale, the ADR was found to be probable.
Conclusions
This case report will help to keep physicians vigilant about the rare cardiac side effects of clozapine and to do regular ECG monitoring of the patients who are on clozapine. Moreover, this case report generates the evidence of clozapine-induced arrhythmia, which is needed to be quantified with aggressive study design and there is a need to study the dose-dependent relationship of clozapine-induced arrhythmia.
The chapter describes the history, mechanisms and phases of drug treatment of antipsychotics including at-risk mental states (ARMS), first-episode psychosis (FEP), maintenance, treatment-resistant schizophrenia (TRS) and ultra-resistant psychosis. Specific treatments of schizoaffective disorder, catatonia and affective comorbidities of psychosis target negative symptoms and cognition. Rapid tranquilisation is described: general principles, de-escalation, routes of administration and medication selection. Management of organic psychotic disorders is discussed: general principles and specific conditions, epilepsy, Huntington’s, stroke, drug-induced, autoimmune encephalitis, inflammatory, CNS infections, thyroid disorders and traumatic brain injury. Side effects are elaborated: somnolence and sedation; hyperprolactinaemia and sexual dysfunction; motor, cardiac, metabolic and anticholinergic side effects; and also diabetes and impaired glucose tolerance and clozapine-specific side effects. Finally, potential drug interactions are explored.
A comparative analysis of combination therapy regimens was carried out in patients with paranoid schizophrenia with NSAA and identified signs of resistance to ongoing neuroleptic monotherapy. In total, in the period from 2015 to 2022, 155 patients with paranoid schizophrenia with NSAA were studied as part of a multicenter randomized longitudinal study. It has been established that the first-line therapy regimen in this group of patients is a combined regimen of clozapine with haloperidol.Introduction. The increase in the number of therapeutically resistant patients with paranoid schizophrenia with auto aggression remains one of the most pressing problems in psychiatry remains as the most common nosological unit [1,2,3]. At the same time, a large amount of research material has been accumulated on the factors and conditions that affect the formation of the state of resistance in such patients [4,5,6,7]. First of all, these include: a debut at an early age, an "erased" beginning, a continuous course, the dominance of negative symptoms in the structure of the pathological process, and the fading of the affective component. A special place among the clinical predictors of therapeutic resistance is occupied by psychopathic disorders with auto aggressive tendencies, traditionally considered within the framework of heboid states. At the same time, until recently, the main drug from the group of neuroleptics used to overcome resistance was clozapine [8,9,10,11,12,13]. In practice, up to 30% of patients remain intact to its action, which dictates the need for combination therapy [14,15,16]. This predetermines the search for new schemes for the use of medicinal drugs to solve this problem.
Safe and effective administration of clozapine requires careful monitoring for inflammatory reactions during the initial titration. The concentration-to-dose (C/D) ratio must be taken into account, which may vary among ethnicities. In this retrospective study, 1408 Korean schizophrenia inpatients were examined for during the first 8 weeks of clozapine titration. The average doses of clozapine administered during weeks 1, 2, 4, and 8 were 77.37, 137.73, 193.20, and 212.83 mg/day, with significantly lower doses for females than males. The average C/D ratio was significantly higher in females (1.75 ± 1.04 and 1.11 ± 0.67 ng/mL per mg/day). Patients with higher C/D ratios were more likely to experience fever and were prescribed lower doses of clozapine starting from week 4. In total, 22.1 % of patients developed a fever at an average of 15.74 days after initiating clozapine. Patients who developed a fever were younger, used more antipsychotics at baseline, had a higher C/D ratio, and had a higher incidence of an elevated C-reactive protein level. A higher C/D ratio, use of a greater number of antipsychotics at baseline, and concomitant olanzapine use were risk factors for the development of inflammatory reactions. The incidence of pneumonia, agranulocytosis, and myocarditis within 8 weeks were 3.7 %, 0.3 %, and 0.1 %. In summary, the target dose of clozapine titration is lower for Korean schizophrenia patients, with a higher C/D ratio and more frequent fever compared to Western patients; however, myocarditis occurs rarely. Our findings may contribute to the titration methods for clozapine for the East Asian population.
Background:
Little information is available on clozapine discontinuation rates in developing country settings.
Aim:
The present study aimed to evaluate the incidence and reasons clinicians stopped clozapinine in patients after initiating treatment with the same. In addition, the study also aimed to assess the rechallenge rate, that is, restarting clozapine after a decision to discontinue the same by the clinicians.
Methodology:
The treatment records of 859 patients started on clozapine were reviewed to identify the patients for whom the clinician stopped clozapine at least once because of any reason. The reasons for stopping clozapine were reviewed. In addition, the treatment records were also examined for rechallenge with clozapine at a later date.
Results:
Clozapine was stopped by the clinicians in 44 of the 859 patients (5.12%). The most common reason for stopping clozapine was blood dyscrasias (n = 12), followed by poor adherence making the hematological monitoring difficult (n = 9), and intolerable sedation (n = 7). In half of the patients (n = 22), clozapine was restarted by the clinicians for further management of schizophrenia. Successful rechallenge was done in 58.33% of patients with blood dyscrasias, 44.44% with poor adherence, and 71.4% with intolerable sedation.
Conclusions:
The present study suggests clinicians stop clozapine in only 5.14% of cases. The most common reasons for clozapine discontinuation by clinicians include blood dyscrasias, poor medication adherence making it challenging to monitor the hemogram, and sedation. However, in half of the patient's clozapine was rechallenged, and all the attempts of rechallenging were successful.
A comparative analysis of combination therapy regimens was carried out in patients with paranoid schizophrenia with NSAA and identified signs of resistance to ongoing neuroleptic monotherapy. In total, in the period from 2015 to 2022, 155 patients with paranoid schizophrenia with NSAA were studied as part of a multicenter randomized longitudinal study. It has been established that the first-line therapy regimen in this group of patients is a combined regimen of clozapine with haloperidol. Introduction. The increase in the number of therapeutically resistant patients with paranoid schizophrenia with auto aggression remains one of the most pressing problems in psychiatry remains as the most common nosological unit [1,2,3]. At the same time, a large amount of research material has been accumulated on the factors and conditions that affect the formation of the state of resistance in such patients [4,5,6,7]. First of all, these include: a debut at an early age, an "erased" beginning, a continuous course, the dominance of negative symptoms in the structure of the pathological process, and the fading of the affective component. A special place among the clinical predictors of therapeutic resistance is occupied by psychopathic disorders with auto aggressive tendencies, traditionally considered within the framework of heboid states. At the same time, until recently, the main drug from the group of neuroleptics used to overcome resistance was clozapine [8,9,10,11,12,13]. In practice, up to 30% of patients remain intact to its action, which dictates the need for combination therapy [14,15,16]. This predetermines the search for new schemes for the use of medicinal drugs to solve this problem.
Treatment-resistant schizophrenia (TRS) poses a significant therapeutic challenge in psychiatric practice. Clozapine is recognized as a treatment of choice in TRS but is not always effective in alleviating patients' symptoms. Additionally, clozapine therapy is associated with multiple side effects and monitoring requirements that often limit its use and negatively affect patients' compliance with the treatment. Although clozapine augmentation options are available, there is currently no alternative monotherapy proven to be effective in TRS. We present a case of a young man with TRS who failed to respond to appropriate trials of risperidone, aripiprazole and also clozapine, and who experienced impairing adverse effects of clozapine that made further clozapine treatment not only futile but also detrimental to his health. He was successfully treated with cariprazine monotherapy, which culminated in the remission of his both positive and negative symptoms of psychosis as well as in the marked improvement in social functioning. Cariprazine, a newer atypical antipsychotic endowed with a D3-preferring mode of action, may offer a better tolerated and more acceptable treatment option for patients with difficult-to-treat psychotic symptoms.
Résumé
Objectifs
L’hypersialorrhée iatrogène correspond à un excès de sécrétion salivaire causé par la prise d’un médicament. Cet effet indésirable, fréquent avec les psychotropes, peut être à l’origine d’une mauvaise observance et nécessite donc une prise en charge optimale.
Méthodes
Les études cliniques et rapports de cas décrivant une prise en charge spécifique de l’hypersialorrhée iatrogène ont été recherchés dans les bases de données PubMed, Google Scholar et Science Direct (mots-clés : « treatment », « hypersalivation », « induced », « drug », « clozapine »).
Résultats
Au total, 67 articles ont été inclus dans cette revue narrative. Les médicaments responsables d’une hypersialorrhée étaient la clozapine (61/67), la rispéridone (3/67), la quétiapine (2/67) et l’aripiprazole (2/67). Le traitement reposait principalement sur des thérapies non médicamenteuses associées à une optimisation de la posologie du traitement incriminé (effet dose-dépendant). Parmi les 63 articles ciblant un traitement correcteur, différentes classes thérapeutiques étaient décrites telles que les anticholinergiques (41/63), les molécules agissant sur les systèmes adrénergique (7/63), dopaminergique (10/63), la N-acétylcystéine (1/63) et la toxine botulique (4/63).
Conclusions
Le niveau de preuve concernant les traitements de l’hypersialorrhée iatrogène reste faible. En l’état actuel des connaissances, on privilégiera les thérapies non médicamenteuses et l’optimisation posologique du traitement responsable. En cas d’échec de ces mesures, un traitement anticholinergique peut être initié après évaluation de la balance bénéfices/risques. Les autres options thérapeutiques doivent être envisagées en dernière ligne, en fonction de la forme galénique, la tolérance et l’accès aux thérapeutiques. Des recommandations pratiques sont présentées dans cet article.
Introduction: Treatment resistant schizophrenia (TRS), affecting approximately one-third of patients with schizophrenia, is associated with a serious impairment in global psychosocial functioning. Clozapine is the only licensed drug for TRS. However its prescription remains limited by its side effects requiring mandatory monitoring. The need to identify clinical factors associated with good response to clozapine in TRS has been established. The presence of ethnic differences in these factors and the scarcity of data on the Tunisian or more generally the North-African population warrants the conduct of a clinical study on the subject. The aim of this study was to investigate demographic, clinical, and biochemical patient characteristics as potential predictors of response to clozapine. Methods: This is a cross-sectional and retrospective study, at the “F and A psychiatry departments” of Razi Hospital in Manouba, Tunisia. All patients, with DSM 5 diagnosis of schizophrenia in its resistant form, on clozapine for at least 12 months and who consulted from June 1, 2018 to November 30, 2018 were included. We investigated premorbid functioning by the premorbid adjusment scale, demographic and clinical characteristics, and clozapine plasma level as potential clozapine response predictors. The response to clozapine was defined by a total BPRS score of 35 or less. Results: Sixty-three patients were included in the study. The mean age at clozapine introduction was 30,84 ±9,25 years. The mean duration of clozapine treatment was 7,22 ± 4,02 years.There were 16 clozapine responders (25%) who had BPRS total scores below or equal to 35 and 47 non-responders (75%).A higher premorbid social functioning in childhood (p = 0,018) and early adolescence (p = 0,024) was associated with better response to clozapine. A delay clozapine initiation shorter than 7 years(p = 0,036), one atypical antipsychotic trial (p = 0,029) and schizophrenia paranoid subtype (p
Objectives:
Safe and efficient methods for introducing clozapine to patients with treatment-resistant schizophrenia (TRS) are needed. We investigated risk factors for clozapine discontinuation in the early phase of its introduction.
Methods:
We conducted a nested case-control study at 14 psychiatric hospitals in Chiba, Japan. Data from pre-registered TRS patients were collected at 7 time points within 12 weeks before and after the start of clozapine introduction. We examined the demographic data, prior and concomitant psychotropic drugs, strategies for switching from prior antipsychotics, and blood test and Global Assessment of Function results. The Clinical Global Impression-Severity Scale was retrospectively scored at 12 weeks before and after clozapine introduction.
Results:
Of 228 patients, clozapine treatment was continued in 213 (93.4 %) and discontinued in 15 (6.6 %) patients within 12 weeks. Clinical symptoms were improved to mild symptoms with a response rate of 14.9 %. Prior antipsychotics and concomitant psychotropic drugs except for mood stabilizers were significantly decreased. Histories of smoking (OR = 3.32, 95 %CI: 1.11-9.93) and antipsychotic treatment at chlorpromazine-equivalent doses <1200 mg within the past 5 years (OR = 3.93, 95 %CI: 1.24-12.50), but not antipsychotic switching strategy, were associated with clozapine discontinuation. Eosinophilia was the most frequent reason for discontinuation (n = 3, 20 %) and was associated with concomitant valproate at 4 weeks after the introduction.
Conclusion:
Clozapine is an effective option for TRS patients (especially those treated with higher doses of prior antipsychotics) in Japan. Clinicians should be cautious about concomitant valproate in the early phase of clozapine introduction due to a high risk of eosinophilia.
No studies have compared clinical outcomes after discontinuation of clozapine between patients who responded to clozapine and those who did not. Therefore, we examined 1-year clinical outcomes after clozapine discontinuation in responders and nonresponders. We reviewed data on patients who discontinued clozapine and retrospectively followed them for 1 year. Clinical information was collected from medical records starting at the initiation of clozapine administration, at discontinuation and at 1 year after discontinuation. In addition, clinical status was assessed using the Clinical Global Impression - Severity (CGI-S) and Clinical Global Impression - Improvement (CGI-I) scales. We classified the patients into clozapine responder and nonresponder groups according to the CGI-I score. Thirty-nine patients were enrolled in this study. Olanzapine was the most common antipsychotic prescribed after clozapine discontinuation in both the responder and nonresponder groups. The mean CGI-S score significantly increased 1 year after clozapine discontinuation in the responder group and significantly decreased in the nonresponder group; there was a significant difference in changes in the CGI-S scores between the groups. The difference remained significant after controlling for clozapine dose and duration of treatment. The findings suggest that clinicians may consider continuing and discontinuing clozapine treatment for patients who responded to clozapine and those who did not, respectively.
Background
To date, there have been no studies evaluating adherence to clozapine with electronic adherence monitoring (EAM) such as the Medication Event Monitoring System (MEMS®).
Methods
In outpatients with schizophrenia, we conducted a 3‐month prospective study investigating antipsychotic adherence with EAM (eCAP®). Participants were treated with different oral antipsychotics, including clozapine, and blind to EAM monitoring; all were on antipsychotic monotherapy administered once daily. Outcome measures included adherence rate, missed dose, and medication gap. Adherence trajectory patterns were also analyzed for clozapine versus other antipsychotics collectively.
Results
A total of 111 patients were included in the study; 33 and 78 patients received clozapine or other antipsychotics, respectively. Adherence rates, defined as proportion of days that the subject took the medication at the prescribed time ±3 h and proportion of subjects with ≥80% adherence, were numerically higher in patients receiving clozapine versus other antipsychotics (72.0% vs. 65.1%, P=0.10; 49.5% vs. 35.7%, P=0.11, respectively). Along similar lines, some of the missed dose and medication gap outcomes were significantly better in patients receiving clozapine versus other antipsychotics. Three adherence trajectory patterns were identified for both clozapine and other antipsychotics, with two shared by both groups (i.e., low adherence with a slight decrease over time; high and stable adherence).
Conclusion
Findings suggest that in patients with schizophrenia clozapine adherence is at least comparable, if not slightly better, compared to other antipsychotics.
Background
One-third of individuals with schizophrenia have treatment-resistant illness. Of these, up to 60% will respond to clozapine treatment.
Aims
This study retrospectively examined clozapine prescribing patterns against National Institute for Health and Care Excellence (NICE) guidelines as treatment-resistant illness emerged in a first-episode psychosis cohort.
Methods
A total of 339 individuals with a first-episode psychosis were included in the study. Clozapine prescribing patterns were compared against the NICE guidelines and the impact of clozapine use on one index of service utilisation (hospitalisation) was assessed.
Results
A total of 32 individuals (9.4%) from the cohort were prescribed clozapine. The mean time to clozapine trial was 2.1 years (SD 1.95; range 0.17–6.25). The mean number of adequate trials of antipsychotic prior to starting clozapine was 2.74 (SD 1.13; range 1–5). Following clozapine initiation, mean hospital admissions per year reduced from 2.3 to 0.3 ( p=0.00). Mean hospital days pre- and post-clozapine also reduced (147 vs. 53; p=0.00). In total, 18 patients discontinued clozapine use during follow-up – 5 temporarily and 13 permanently.
Conclusions
Patients are being prescribed clozapine earlier than previously demonstrated, though delays are still evident, and many patients discontinue treatment. More work needs to be undertaken to understand and address factors which lead to its discontinuation.
Aim:
Research in patients with treatment-resistant schizophrenia has demonstrated that clozapine discontinuation is associated with poor outcomes. There is, however, a paucity of research investigating the impact of clozapine discontinuation specifically in younger patients with more recent onset schizophrenia. A case note review was therefore conducted to ascertain medium-term prognoses in patients with treatment-resistant schizophrenia under an early intervention service (EIS) following clozapine discontinuation.
Methods:
The case notes of 25 patients under the care of Birmingham EIS who discontinued clozapine were examined retrospectively. Reasons for discontinuation were recorded. Clinical outcomes including total duration of inpatient or home treatment admission, antipsychotic dose, number of alternative antipsychotics prescribed and adverse events were recorded for both the year before and the year after stopping clozapine. Statistical comparisons of pre- and post-discontinuation clinical outcomes determined whether discontinuation had negative effects.
Results:
There was no significant difference between the pre- and post-discontinuation clinical status following clozapine discontinuation. More than half (56%) of patients remained stable after stopping clozapine. Mean inpatient or home treatment stay rose from 29.7 to 62.6 days (p = 0.155), total antipsychotic dose from 50.1% of British National Formulary (BNF) limits to 60.5% (p = 0.627), number of alternative antipsychotics prescribed from 1.28 to 1.80 (p = 0.186), number of hospital/home treatment episodes from 0.20 to 0.44 (p = 0.083) and number of adverse events from 0 to 0.20 (p = 0.059). Non-compliance was the main reason for discontinuation (44%, n = 11).
Conclusions:
This is the first clozapine discontinuation study specifically considering EIS patients. Discontinuation did not lead to significant effects on 1 year outcomes, though the study is underpowered. These findings may be used to inform future prospective cohort discontinuation studies.
Objective:
Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.
Method:
A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus.
Results:
Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients.
Conclusions:
There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.
Background:
Clozapine 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.
Methods:
We 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.
Results:
A 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).
Conclusions:
Living 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.
To study the prevalence and incidence of seizures in patients prescribed clozapine.
The treatment records of 222 patients commenced on clozapine were retrospectively reviewed during the period of January 2007 to June 2014 to evaluate the prevalence of seizures before and after starting clozapine.
The majority of patients commenced on clozapine were male (65%), single (65%), and unemployed (57%). The mean (± standard deviation) dose of clozapine was 277.9 ± 102.5 mg/day. A history of seizure was present in 6 patients who were also prescribed antiepileptic medication; of these 6 patients, only 1 case had recurrence of seizure while taking clozapine due to poor compliance with ongoing antiepileptic medication. The incidence rate of new-onset seizure with clozapine was 6% (12/216). Most patients who developed seizures were male, aged between 24 and 41 years, and had a long duration of illness (≥ 10 years). The risk of seizure was associated with the dose of clozapine used: 3% (5/159) with dose up to 300 mg/day, 8% (4/49) with 325 to 500 mg/day, and 38% (3/8) in those receiving > 500 mg/day. More than half of the patients (7/12) who developed seizures while prescribed clozapine were managed with reduction in the dose of clozapine. In one-third of cases (4/12) an antiepileptic medication was added and in 1 case, clozapine was stopped. All patients who continued on clozapine remained seizure-free at follow-up that ranged from 6 months to 4 years.
The incidence of seizures with clozapine was 6% and the risk of seizures increased with higher doses.
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.
The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack of clarity about its risk benefit ratio. This review synthesises and evaluates available evidence regarding the efficacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making.
We conducted a systematic review of the primary literature on the clinical efficacy and adverse drug reactions (ADRs) observed during CLZ treatment in EOS. We also identified relevant practice guidelines and summarised current guidance.
CLZ showed superior efficacy than other antipsychotics in treating refractory EOS patients; short-term clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported. Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specific EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes in blood pressure. Neutropenia was reported in 6-15% of cases but was usually transient while agranulocytosis was rare (<0.1%). Seizures were also uncommon (<3%). Metabolic changes were relatively common (8-22%) but emergent diabetes was not frequently observed (<6%). Overall the rate of discontinuation was low (3-6%). Current guidelines recommend the use of CLZ in EOS patients who have failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment.
Available data although limited in terms of number of studies are consistent in demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided patients are regularly monitored.
The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.
A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments.
Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.
The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.
Purpose/background:
Cessation of clozapine therapy and insufficient response may result in relapse of psychotic symptoms and in clinical admissions. However, discontinuation rates are high. Identifying patients at risk for unsuccessful clozapine use might enable clinicians to direct specific attention to them.
Methods/procedures:
Routinely collected data from a large insurance company were used to develop a simple prediction model for unsuccessful clozapine treatment in psychiatric patients 1 year after clozapine was first dispensed by a community pharmacy in the Netherlands. Multivariate logistic regression analyses were performed with the Nagelkerke R statistic as a measure of the predictive value of the model.
Findings/results:
A total of 937 patients were dispensed clozapine for the first time by their community pharmacy between January 1, 2011, and December 31, 2015 (index date). Of these, 741 patients had started their clozapine treatment in hospital before the index date (inpatient starters); the remaining 196 patients started clozapine as outpatients on the index date (outpatient starters). In 191 patients (20.4%), clozapine treatment was unsuccessful 1 year after the index date. Unsuccessful treatment was more common among outpatient starters than among inpatient starters (32.1% vs 17.3%). Using backward selection of the variables, a model consisting of 61 variables had the best predictive value overall (Nagelkerke R = 0.301), whereas a model consisting of 52 variables had the best predictive value in outpatient starters (Nagelkerke R = 0.676).
Implications/conclusions:
The likelihood of unsuccessful clozapine treatment after 1 year was higher among patients who started clozapine as outpatients. Despite the use of a diversity of variables and different statistical approaches, it was not possible to make a simple prediction model for unsuccessful clozapine treatment using relatively easily accessible data.
Objective:
The aim of this study was to investigate clozapine use and its associated adverse effects in patients in Japan.
Methods:
We analyzed data recorded from July 2009 to January 2016 (N = 3780 patients) in the Clozaril Patient Monitoring Service, which was established in Japan in 2009 and includes all Japanese patients who have been prescribed clozapine.
Results:
The treatment discontinuation rate was 23.9% (869/3780 cases). The average ± SD treatment duration was 234.9 ± 306.9 days (median, 115 days), and the average ± SD dosage was 186.41 ± 151.6 mg/d. The estimated treatment continuation rates resulting from all-cause discontinuation were 78.2 after 1 year and 72.9% after 2 years of treatment. The incidence of neutropenia/leucopenia was 5.4% (206/3780 cases). The average ± SD dose before discontinuation was 233.36 ± 168.15 mg (median, 200 mg; range, 4-600 mg). The incidence of glucose intolerance was 15.4% (583/3780 cases). Of 3780 patients, 98 (2.67%) developed glucose intolerance before and after taking clozapine administration, whereas 485 patients (12.8%) developed glucose intolerance after taking clozapine. The average ± SD time from treatment initiation to new onset of glucose intolerance was 382.2 ± 420.2 days (median, 216 days; range, 4-2053 days).
Conclusions:
The data obtained in this study, particularly regarding the incidence of clozapine-induced adverse events, will enable the optimal and safe use of clozapine in Japanese patients with treatment-resistant schizophrenia.
Objective:
Clozapine is uniquely effective for treatment-resistant schizophrenia, and so treatment continuation is essential. We aimed to identify factors associated with an increased likelihood of clozapine discontinuation in a cohort of patients in South East London.
Methods:
We gathered demographic and treatment information such as duration of illness and antipsychotic treatment history. t-tests, chi-square tests and binary logistic regression were used to compare patients who continued and discontinued clozapine during the study and to identify predictor variables for discontinuation.
Results:
Out of the study population of 133 patients, 48 discontinued clozapine at least once during the study period. The majority of these (75%) stopped treatment within the first 4 years of clozapine therapy. Age, ethnicity, diagnosis and antipsychotic treatment history were not predictive of the risk of clozapine discontinuation. However, male patients were more likely to stop taking clozapine (χ2 = 6.81, p = 0.009). The odds of discontinuing clozapine were 2.15 times higher for male patients. The most common reason for discontinuation was patient refusal of treatment.
Conclusion:
We found that patients who discontinue clozapine are more likely to be male, but no other demographic variable was found to predict treatment cessation. Discontinuation usually occurred due to patient refusal of treatment.
Clozapine is the most effective antipsychotic for the 25% to 33% of people with schizophrenia who are treatment resistant, but not all people achieve response. Using data from a previously published clozapine systematic review and meta-analysis, we explored the proportion of people who achieved response and examined the absolute and percentage change in Positive and Negative Syndrome Scale (PANSS) scores. Overall, 40.1% (95% confidence interval [CI], 36.8%-43.4%) responded, with a mean reduction in PANSS of 22.0 points (95% CI, 20.9-23.1), a reduction of 25.8% (95% CI, 24.7%-26.9%) from baseline. These reductions are clinically meaningful. A 40% response rate to clozapine suggests that 12% to 20% of people with schizophrenia will be ultra-resistant.
Background Although clozapine is the 'gold standard' for treatmentrefractory schizophrenia, meta-analyses of clozapine for this condition are lacking. Aims We conducted a systematic review and meta-analysis of clozapine treatment for people with treatment-refractory schizophrenia. Method We searched the Cochrane Schizophrenia Group's trial register, PubMed and EMBASE and hand-searched key papers for randomised controlled trials of clozapine for treatment-refractory schizophrenia. Results Twenty-one papers with 25 comparisons were included. The number needed to treat was 9. Clozapine was superior for positive symptoms in both the short and long term. In the short term only clozapine was superior for total and negative symptoms, with higher response rates. Both funding source and dosage affected results. Higher baseline psychosis scores predicted better outcomes for clozapine in a meta-regression. Conclusions Clozapine is superior for treatment-refractory disorder but if there is no response by 6 months medications with lower adverse reactions should be considered. Declaration of interest None.
Consensus guidelines which are applicable in New Zealand and worldwide recommend that the duration of exposure to antipsychotics not exceed 12 weeks, unless justified for mental illnesses like schizophrenia and severe psychotic symptoms which require longer treatment. There has been limited information on time-to-first discontinuation (TTFD) for second-generation antipsychotics (SGAs) in a real world population setting in older people. The study objective was to compare TTFD, adherence, and persistence for individual SGA new users among people 65 years and older. A cohort of 30,297 SGA new users was followed up for antipsychotic discontinuation from January 1, 2006, to December 31, 2012. Data for oral formulations were extracted using health care databases from the New Zealand Ministry of Health. The TTFD, adherence, and persistence were defined using (dispensing gap >= 91 days, variable medication possession ratio >= 0.8, and gap duration < 91 days between refills), respectively. Kaplan-Meier curves and Cox regression analysis were used to estimate and adjust for outcomes. The overall TTFD in SGA new users was 192.3 days (95% confidence interval [CI], 177.6-206.9), mean age at dispensing was 80.9 years (SD, 8.1 years), and 60.3% were women. The TTFD for was shortest for risperidone, 101.3 days (95% CI, 85.0-117.7; P = 0.03) compared with clozapine, 68.3 days (95% CI: 43.7, 92.9). The adjusted all-cause TTFD risk for risperidone, olanzapine, quetiapine, or ziprasidone (hazard ratios, 0.54, 0.29, 0.22, and 0.08, respectively) was significantly lower than clozapine. The TTFD risk in the non-adherent compared with the adherent group was more than 3 times.
Background:
Clozapine is a second-generation antipsychotic that has been shown to reduce suicidal ideation and suicidal behaviors in patients with schizophrenia. However, it is underutilized because of its serious side effects.
Methods:
We describe 3 patients with a history of suicide ideation and attempts who were successfully treated and maintained in the community without suicidal tendencies while taking clozapine. All 3 patients, men in their 20s, discontinued clozapine because of side effects and subsequently committed suicide. We also review the literature on clozapine's effects on suicidality.
Results:
In these 3 cases, suicide followed abrupt discontinuation of clozapine or transition to another antipsychotic.
Conclusions:
This case series is the first of its kind to document the risk of suicide when clozapine is discontinued. The decision to discontinue clozapine should be made carefully, especially because clozapine is considered the treatment of last resort for patients with treatment-resistant schizophrenia and suicidal ideation. We stress the importance of minimizing the risk of abrupt clozapine discontinuation and recommend further evaluation of suicide ideation and attempts when clozapine is discontinued.
Background: Clozapine is uniquely effective in refractory schizophrenia, but treatment attrition is high. There has been minimal formal study of the outcomes of stopping clozapine, beyond published observations of the time period immediately after cessation. Our aim was to establish medium-term outcome in patients stopping clozapine in normal clinical practice. Method: This study was a retrospective analysis of all subjects registered with Clozaril Patient Monitoring Service and treated in South London and Maudsley National Health Service (NHS) Trust who stopped clozapine between March 2002 and March 2005 after at least I year's treatment. Case note review was performed to determine relevant information for I year before and I year after discontinuation of clozapine, including subject details, reasons for stopping, and clinical outcome I year after discontinuation. The primary outcome measure was the Global Assessment of Functioning scale. Results: Thirty-five patients met inclusion criteria. Twelve had died while receiving clozapine. Of those followed up for I year after cessation (N = 23), mean Global Assessment of Functioning scores fell by 15 points (95% CI = 6.6 to 24.3; p =.002). Days spent in hospital rose from a mean of 74.1 (SD = 137.3) to 119.8 (SD = 143.5) (p =.214). Conclusion: Discontinuation of clozapine has a marked negative impact on clinical status. Death is a common cause of clozapine cessation.
Introduction: Clozapine is the most effective treatment for treatment-resistant schizophrenia but its use is suboptimal. Methods: Clozapine dispensing data from Queensland, Australia were extracted (2004-2013). The number of people dispensed clozapine each year and mean maintenance doses were calculated. The 18-week and 5-year cessation and treatment interruption rates were calculated using Kaplan-Meier analysis. Results: Clozapine dispensings increased 36.4% (p<0.001) from 44 to 60 people per 100 000. This was estimated as 8.3% of people with schizophrenia and 33.3% of people with treatment resistant schizophrenia dispensed clozapine in 2013. Mean maintenance dose did not significantly change (364-399 mg) over 5 years of treatment. One in 7 (14.2%) people ceased within the first 3 weeks. 3-quarters (72.7%) reached maintenance therapy. The 5-year actuarial estimate of the proportion of people a) dispensed clozapine was 0.610 (S.E. 0.011) and b) with an interruption to treatment was 0.422 (S.E. 0.013). Discussion: The number of patients being dispensed clozapine increased between 2004 and 2013 but clozapine is still underused. Increased use combined with continued monitoring for adverse effects will improve quality use of clozapine.
© Georg Thieme Verlag KG Stuttgart · New York.
Introduction:
The clinical records of 190 patients with schizophrenia who discontinued clozapine between 1990 and 2012 in the county of Northamptonshire were examined, in an attempt to answer the following questions. Why do patients stop clozapine? What do physicians prescribe as an alternative? What is the mortality in this patient group?
Methods:
Patients' data were extracted using their electronic records, then analysed using descriptive statistical methods.
Results:
Non-compliance with treatment, or with the mandatory white blood cell monitoring, was the most common reason (55.3%) for clozapine cessation, followed by neutropaenia and other adverse effects (25.2%). Death (mean age 48 years) was the third most common reason (10%), with respiratory infections accounting for more than a quarter of the deaths. 13% of the patients had died (mean age 49 years) at some point following clozapine discontinuation. In terms of the alternative antipsychotic prescribing, olanzapine was the most commonly prescribed (37.1%) drug in patients who were still under the care of the local psychiatric service (n=121), at the time of data extraction. Clozapine had been reinstated in 19% of these patients.
Discussion:
Our findings are generally consistent with previous studies, and they demonstrate the need for physicians to address their patients' concerns regarding clozapine treatment, and to effectively manage any adverse effects. Sialorrhea and constipation seem to be particularly of concern, as they may be linked to clozapine- related mortality. Olanzapine was the most commonly prescribed alternative to clozapine, which suggests that it may possibly have a role in refractory schizophrenia.
To identify the outcome of potentially serious adverse effects of clozapine, particularly those frequently cited as reasons for clozapine discontinuation, and to characterize management strategies for adverse effects that do not warrant discontinuation.
A structured search was performed of PubMed and EMBASE from database inception until September 10, 2012, without any language restrictions, using clozapine as the search term. Reference lists of retrieved articles were cross-checked for additional relevant studies.
Included in this review were studies that reported on the frequency of the specified clozapine-related adverse effects and that either reported on the grounds for or against clozapine discontinuation or reported on management techniques to maintain patients on clozapine or enable successful clozapine rechallenge. The following side effects were considered important for this review as potential grounds for clozapine discontinuation: neutropenia or agranulocytosis, leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, leukocytosis, QTc prolongation, electrocardiogram changes, atrial flutter, tachycardia, myocarditis, cardiomyopathy, fever, syncope, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma, neuroleptic malignant syndrome, ileus, liver enzyme elevation, or seizure.
Study results that supported continuation or discontinuation of clozapine or that provided information on management techniques were abstracted.
Of a total of 13,385 search results, data from 81 studies were included in this review. Results suggest that prompt discontinuation of clozapine without rechallenge is indicated for agranulocytosis, myocarditis, cardiomyopathy, and a QTc interval > 500 milliseconds that is confirmed and derived using the appropriate correction method. Clozapine discontinuation with potential rechallenge (provided there is appropriate surveillance and management or prophylactic therapy) is indicated for ileus or subileus, neuroleptic malignant syndrome, venous thromboembolism, and diabetic ketoacidosis or hyperosmolar coma. Neutropenia, leukocytosis, seizures, orthostatic hypotension, severe constipation, and weight gain and metabolic abnormalities, including metabolic syndrome and its components, as well as moderately prolonged myocardial repolarization, need to be managed but do not generally warrant clozapine discontinuation. Eosinophilia, leukocytosis, drug-induced fever, and tachycardia (provided that myocarditis and neuroleptic malignant syndrome are ruled out) can be managed and should rarely lead to clozapine discontinuation.
A number of side effects commonly cited as medical reasons for clozapine discontinuation do not necessarily warrant such action. Management techniques are available that allow continuation or rechallenge in relation to a number of clozapine-related side effects.
Background:
Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians.
Aims:
To determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment.
Method:
Clinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010.
Results:
Complete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (β = 0.7, P<0.001) but did not differ by gender or ethnicity.
Conclusions:
Substantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.
Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory schizophrenia is clozapine. However, a significant number of patients cease clozapine therapy; therefore this study explores patient's motives for cessation.
The motives for cessation and duration of clozapine treatment from a retrospective database of 151 patients with schizophrenia or schizo-affective disorder who had ceased clozapine once or more were reviewed, with the motives for cessation coded. The general motives for cessation were non-compliance, own decision, medical, poor response and other. In addition, the medical reasons for cessation were further codified: cardiac complications, neutropenia, fevers, other side effects and pregnancy.
The majority of patients ceased clozapine owing to non-compliance with medical protocols or citing their own decision. Approximately half ceased after a period of 6 months or less. Seventeen per cent of patients ceased owing to medical reasons, with the largest proportions discontinuing treatment because of other side effects or neutropenia.
Future research should seek to further investigate why patients decide to be non-compliant and formulate their own decision to cease treatment, as this will facilitate strategies to promote adherence amongst these two groups that are potentially the most amenable to change.
Clozapine has superior efficacy for treating patients with schizophrenia. Its discontinuation could have detrimental consequences. We attempted to identify the clinical parameters that could predict clozapine discontinuation in patients diagnosed as having schizophrenia by conducting a retrospective analysis of all of those who started on clozapine treatment during their hospitalization in our institution between 2002 and 2008 (n=100). Demographic and clinical parameters were analyzed and compared between the 58 patients who continued and the 42 who discontinued clozapine treatment during a follow-up period of 8.1 years. Twenty of the latter patients (47.6%) discontinued clozapine because of nonadherence and 11 (26.2%) because of side effects. Thirty-three of them (78.6%) stopped taking clozapine during the first year of treatment. The duration of clozapine use correlated significantly with the time to readmission (P<0.001). The decrease in number of suicide attempts was higher in those who continued clozapine treatment compared with those who discontinued it (P=0.02). Predictors for drug discontinuation were old age at clozapine initiation and comorbid substance abuse. These findings indicate that patients with schizophrenia with those risk factors need special incentives to be compliant during the first year of clozapine treatment to minimize the negative sequelae of clozapine discontinuation.
The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.
Antipsychotic medication maintenance and the factors influencing it were analyzed using data from the SOHO study, a large observational study of the outcomes of antipsychotic treatment for schizophrenia in Europe. A total of 7186 adult patients in the outpatient setting who were initiating or changing their antipsychotic medication and who were prescribed only one antipsychotic after the baseline visit were analyzed. Medication maintenance at 12 months varied with the type of antipsychotic prescribed, being highest with clozapine (79.5%) and olanzapine (77.0%), and lowest with quetiapine (51.4%) and amisulpride (58.2%). Multiple logistic regression analysis demonstrated that the type of antipsychotic prescribed at baseline was the most important predictor of medication maintenance. Alcohol dependency, taking mood stabilizers, compulsory admission or arrest in the previous 6 months, greater clinical severity, and changing antipsychotic medication due to lack of effectiveness at baseline predicted a higher frequency of medication discontinuation in the subsequent 12 months. In contrast, medication maintenance was higher among patients who were treatment naïve at baseline, socially active or who had loss of libido at baseline. The findings from this study should be interpreted conservatively because of its non-randomized observational design.
There are few independent studies comparing atypical or second-generation antipsychotics (SGAs).
To compare the patterns of use and discontinuation of commonly used SGAs.
Retrospective review of 11,250 case records (2002-2005) of all mental health care contacts in a discrete geographical setting in Scotland. Patterns of use, mean dose, psychotropic co-prescription, duration of treatment, discontinuation rates, and admission rates were examined for amisulpride, clozapine, olanzapine, quetiapine, and risperidone.
Clozapine had a significantly lower discontinuation rate in individuals with schizophrenia, compared to the other 4 SGAs. Off-license prescribing and polypharmacy were common.
SGAs are variously used for schizophrenia and mood disorder and have heterogeneous outcomes, with clozapine being most effective in this study. Independent observational studies such as this complement randomized controlled trials.
- A Ucok
A. Ucok, et al.
Psychiatry Research 275 (2019) 149-154
Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine
- J Kane
- G Honigfeld
- J Singer
- H Meltzer
Kane, J., Honigfeld, G., Singer, J., Meltzer, H., 1988. Clozapine for the treatment-resistant
schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen.
Psychiatry 45, 789-796.
Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia
- A Ucok
- U Çikrikçili
- S Karabulut
- A Salaj
- M Öztürk
- Ö Tabak
Ucok A., Çikrikçili U., Karabulut S., Salaj A., Öztürk M., Tabak Ö., et al. Delayed initiation
of clozapine may be related to poor response in treatment-resistant schizophrenia.
Int. Clin. Psychopharmacol. 30,290-295.
The Guideline for Treatment of Schizophrenia. Publication of Psychiatric Association of Turkey
- A Ucok
- H Soygur
Ucok, A., Soygur, H., 2010. The Guideline for Treatment of Schizophrenia. Publication of
Psychiatric Association of Turkey, Ankara.