Superiority Of Clozapine Research Articles

A scoping review of literature on clozapine from former USSR states published in Russian language

ObjectiveAccess to literature on clozapine in Russian language remains strikingly limited. We aimed to identify and translate clinical evidence on clozapine-based treatment outcomes. MethodsWe performed a systematic review in PubMed, Embase and scientific indexes from former USSR states searching for articles published in Russian from the database inception till January 2023 and summarized the data in a scoping review (PROSPERO Reg. Number CRD42023386737). ResultsA total of 60 papers were included comprising eight main topic categories: 1) clozapine-related intoxications (n = 20), 2) effectiveness/efficacy and safety of clozapine treatment (n = 14), 3) adverse drug-induced reactions (ADRs) related to clozapine treatment (n = 9), 4) therapeutic drug monitoring for clozapine (n = 5), 5) combination of clozapine and non-pharmacological treatments (n = 4), 6) pharmacoepidemiology of clozapine (n = 3), 7) effects of clozapine on the brain electrical activity (n = 3), and 8) novel clozapine formulations (n = 2). Among clozapine-related intoxications there were reports of criminal poisoning, which was associated with low lethality. Worse outcomes were accompanied by systemic reactions to intoxications. Clinical benefits of hemoadsorption were reported in the management of clozapine-related intoxications. Only half of studies reporting clozapine effectiveness used standardized scales to assess outcomes. Clozapine superiority in treatment-resistant schizophrenia (TRS) was replicated in one trial. No reports of clozapine-related agranulocytosis were identified. Clozapine ranked among most prescribed antipsychotics for TRS and non-TRS. ConclusionsAs clinical research in former USSR states is advancing to adopt western clinical research standards, comparability and extrapolation of findings is expected to increase, with transfer of older findings to clinical practice being particularly challenging.

Iranian psychiatrists’ attitude towards clozapine use for patients with treatment-resistant schizophrenia: a nationwide survey

BackgroundClozapine has the greatest efficacy for treatment-resistant schizophrenia (TRS), even though its underutilization is not uncommon across different countries. This study aimed to investigate the knowledge and attitude of Iranian psychiatrists toward clozapine use.MethodIn this cross-sectional study, a questionnaire was distributed among psychiatrists registered with the Iranian Psychiatrists Association (including its provincial branches) to assess their knowledge and attitude towards clozapine use. A total of 282 psychiatrists completed the questionnaire. Descriptive analysis was used to describe demographic information, and Chi-square tests were conducted to determine if there is an association between academic position and work experience. All statistical analyses were performed using SPSS® version 25.0 for Windows, and a significance level of 0.05 was used.ResultsMost respondents (93%) acknowledged that they prescribed clozapine for their patients, and 74% believed that clozapine was more effective than other antipsychotic drugs. However, 43.3% of the respondents said they did not believe in the safety of clozapine. Difficulty initiating and having no firsthand experience in the superiority of clozapine were reported by 81.2 and 80% of the respondents, respectively. Our results also showed an association between having an academic position and access to appropriate facilities for the control and management of patients treated with clozapine and believing in the safety of clozapine (p < 0.05). Longer work experience (more than 15 years) was associated with a higher prescription of clozapine, belief in greater effectiveness of clozapine, and its safety (p < 0.0001).ConclusionIranian psychiatrists had a good self-perception of knowledge about the efficacy of clozapine for patients with TRS, but concerns about serious side effects are common. Psychiatrists with longer work experience and academic positions were more optimistic towards clozapine use than the younger ones with no academic position. Considering the results in planning the strategies to decrease concerns about clozapine use is recommended.

Effect of age on the relative efficacy of clozapine in schizophrenia.

Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P=0.79 CI -0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use.

Clozapine as a first‐ or second‐line treatment in schizophrenia: a systematic review and meta‐analysis

ObjectiveNo consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta‐analysis therefore focus on the use of clozapine as first‐line or second‐line treatment in non‐treatment‐resistant patients.MethodsArticles were eligible if they investigated clozapine compared to another antipsychotic as a first‐ or second‐line treatment in non‐treatment‐resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random‐effects meta‐analyses.ResultsFifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta‐analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges’ g = 0.220, P = 0.026, 95% CI = 0.026–0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges’ g = 0.274, P = 0.030, 95% CI = 0.027–0.521).ConclusionThe few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first‐ or second‐line treatment. Only large clinical trials may comprehensively probe disease stage‐dependent superiority of clozapine and investigate overall tolerability.

41. RECONSIDERING THE EVIDENCE FOR CLOZAPINE FOR TREATMENT REFRACTORY SCHIZOPHRENIA

Overall : The superiority of clozapine for treatment refractory schizophrenia was, until very recently, seen as one of the few unshakeable truths in psychiatry. But the pre-eminence of clozapine has recently been called into question by meta-analyses. What are we to make of the fact that meta-analyses of clinical trials, supposedly the pinnacle of evidence based medicine, fail to show an effect which seems clearly evident to most clinicians, and on which many of our guidelines are based? Have we believed in a fairytale for the past three decades? Or do biases in RCTs and methodological limitations of meta-analyses explain the results? These questions will be discussed by Dan Siskind.Another way to address the question of efficacy is to examine the pharmaco-epidemiological evidence using population-based registers. Jari Tiihonen will present data from his seminal studies of mortality and readmission rates under clozapine treatment versus other antipsychotics, as well as other data. These data seem to show powerful positive effects of clozapine at the population level. Furthermore, more recent evidence suggests a role for clozapine in reducing rates of violent offending, with new data presented for the first time by Vishal Bhavsar.Finally, despite clinical guidelines recommending the use of clozapine, the actual rates of clozapine use are much lower than expected, with large regional and international variations. There is evidence that the burden of blood monitoring deters physicians from prescribing clozapine. Yvonne van der Zalm will present new data from a cluster randomised trial testing the efficacy and safety of an intervention to increase rates of clozapine prescribing by employing nurse practitioners trained in the initiation and monitoring of clozapine.John Kane, author of the first, seminal RCT of clozapine in 1988, will lead the discussion.

Treatment of adolescents with early-onset schizophrenia spectrum disorders

We aimed to review literature on the efficacy and tolerability of psychosocial and psychopharmacological interventions in youth with early-onset schizophrenia spectrum disorders (EOS). A rationale for pragmatic psychopharmacology in EOS, including dosing, switching and adverse effect monitoring and management, is provided. Three randomized controlled trials (RCTs) over the last 8 years demonstrated benefits of psychosocial interventions (i.e. psychoeducation, cognitive remediation, cognitive behavioural therapy) for EOS without clear advantages of one psychosocial treatment over another. Six large, placebo-controlled, short-term RCTs over the last 4 years demonstrated that aripiprazole, olanzapine, paliperidone, quetiapine and risperidone, but not ziprasidone, were superior to placebo. Except for clozapine's superiority in treatment-refractory EOS, efficacy appeared similar across studied first-generation and second-generation antipsychotics, but tolerability varied greatly across individual agents. Antipsychotics are efficacious in the treatment of EOS. Given the lack of efficacy differences between antipsychotics (except for clozapine for treatment-refractory EOS), we propose that tolerability considerations need to guide choice of antipsychotics. Further and longer-term efficacy and effectiveness studies are urgently needed that should also explore pharmacologic and nonpharmacologic augmentation strategies.

Clozapine is gold standard, but questions remain

In their recent publication, Frogley and colleagues have reviewed the evidence indicating that clozapine treatment reduces aggressive behaviour in patients with schizophrenia, and perhaps with other disorders as well (Frogley et al. 2012). Although randomized controlled trials testing this anti-aggressive effect are relatively scarce, the evidence based on many studies supports it. There is general agreement on the superiority of clozapine's anti-aggressive effect in schizophrenia, as reflected for example in published expert consensus guidelines (Kane et al. 2003, p. 38) and in standard textbooks (Volavka et al. 2012). However, there are issues that are not quite as clear. Failure to respond to clozapine is one of these issues. In the general population of schizophrenia patients with treatment-resistant illness, only about 50% of patients respond to clozapine (Lieberman et al. 1994). The proportion of responders to clozapine in the treatment of aggression in schizophrenia has not been reliably established, but it is clear that not all patients will respond. The data published by Krakowski et al. (2006) probably represent the most robust support for the anti-aggressive superiority of clozapine over other antipsychotics in schizophrenia. The statistical analyses used in that paper (Krakowski et al. 2006) were not designed to define the outcome in dichotomous terms (response vs. non-response). However, the published interquartile ranges strongly suggest that non-responders to clozapine were present. Similar variability of response to clozapine was observed in other studies. The causes of this variability of response are not well understood. In a follow-up paper, Krakowski & Czobor (2012) demonstrated that the superiority of clozapine was probably not due to its effect on executive functioning. The variability of response is therefore apparently attributable to other factors than cognitive performance. One reason for this variability is that aggressive behaviour in schizophrenia is …

Clozapine is underutilized.

I read the piece by Wang and Li[1] with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory schizophrenia and clinically significant suicidality. Despite the evidence that 25-40% of patients with schizophrenia would be candidates for clozapine based on labeled indications, approximately 5% of patients with schizophrenia are receiving it. Clozapine was approved by the Food and Drug Administration in the United States in 1989 following a large-scale clinical trial we conducted in 1988[2] demonstrating clozapine's superiority over chlorpromazine in carefully selected treatment refractory patients who had undergone a prospective trial of high dose haloperidol in order to confirm their lack of response. Over the subsequent two decades clozapine's superiority has been confirmed in several government-funded studies.[3]–[5] Despite the introduction of other so called ‘atypical’ or second generation antipsychotics, no other compound—even those with similar chemical structures—has consistently replicated clozapine's effects. Although clozapine has been shown to be superior in patients who have failed on other medications, there is no evidence that clozapine is superior as a first-line medication. At the same time, however, it is possible that waiting until a patient fails adequate trials of three different medications is too conservative an approach; these patients may be waiting too long to try an effective treatment. Unfortunately, there is insufficient research to establish the optimum point in an individual's treatment history to introduce clozapine. It is certainly possible that the introduction of clozapine after one fully adequate failed trial of an antipsychotic medication (with confirmed adherence and therapeutic blood levels) would be sufficient. If this proved true it would be particularly valuable in the first episode of illness or in the first years after onset of illness as it would increase the likelihood of a timely treatment response. Clozapine's use has been somewhat constrained by the requirement for weekly blood monitoring in order to detect the presence of agranulocytosis. The risk of true agranulocytosis appears to have declined since the early years of clozapine use, and new methods for managing this condition has reduced fatality rates enormously. Nevertheless, the management of clozapine's side effects continues to be a challenge. Though progress is being made in identifying individuals at high risk for agranulocytosis[6] this still remains an obstacle for some physicians and patients. The risk of metabolic side effects is also very real and needs to be considered in any management plan. The appropriate or optimum dosing of clozapine also remains a challenge. Dosage patterns vary considerably from country to country. Though some studies provide guidance regarding therapeutic blood levels it is likely that there are ethnic differences in these relationships as well. Clearly, as suggested by Wang and Li,[1] more research is necessary to achieve the goals of personalized medicine in the use of a drug like clozapine, where both the potential rewards and risks are higher than usual. Some clinicians and policy makers attribute the underutilization of clozapine to its side effect profile and, therefore, patient resistance to its use. However, it is often the case that physicians project their own concerns about the possible serious side effects of clozapine onto patients and make assumptions about patients' desires without an appropriate process of shared decision-making. Moreover, many physicians in the United States and in China appear more comfortable with antipsychotic drug polypharmacy than with clozapine monotherapy, despite the fact that polypharmacy has not been adequately established as an appropriate strategy for the treatment of refractory patients. The fact that clozapine utilization varies as much as it does from country to country underscores the variety of factors that contribute to its use. Many clinicians are inadequately informed about the evidence base for the use of clozapine and about the strategies necessary for managing its potential adverse effects. Further training about clozapine is necessary. But there is also a need for research on implementation. How can the field of psychiatry better succeed at promulgating the use of evidence-based practices?

Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia.

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D2 receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and “high-dose” olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

Suicidality in schizophrenia: a review of the evidence for risk factors and treatment options.

Suicide is a major contributor to the morbidity and mortality of schizophrenia, accounting for approximately 10% of deaths in these patients. The known risk factors for suicide in schizophrenia include prior suicide attempts, substance abuse, male sex, onset during first decade of illness, social isolation, depression, and feelings of hopelessness. There is significant evidence suggesting that clozapine reduces the suicide rate in patients with schizophrenia and schizoaffective disorder. Possible factors that lead to a decrease in suicidality with clozapine include the following: a direct antidepressant action, improved cognitive function and insight, diminished negative symptoms, reduced substance abuse, and improved compliance. These effects may converge or lessen feelings of hopelessness and more of its converse optimism. The International Suicide Prevention Trial (InterSePT) is a large prospective, 2-year randomized trial of the comparative effects of clozapine and olanzapine involving 980 patients at high risk for suicide in 11 countries in 56 sites. The study included complete freedom to augment these treatments if needed, blinded ratings, a blinded Suicide Monitoring Board, and equivalent clinical contact. The results support the superiority of clozapine over olanzapine to reduce the risk of suicidality and suggest its use should be considered for all patients with schizophrenia with high risk for suicide.

Influence of methodology on outcomes of randomised clozapine trials.

The aim of this study was to clarify the impact of various methodological quality factors on reported outcome of randomised clozapine trials. Trials comparing the atypical antipsychotic clozapine with other antipsychotic drugs were identified in extensive electronic searches. Two independent reviewers extracted data on methodology and primary outcomes, and assessed trial quality by use of three sets of criteria (Cochrane, Delphi, and Jadad). There was no association between trial quality, as measured by any of the criteria sets, and primary measures of outcome. Trials with the best score for randomisation and concealment according to the Delphi scale had a significantly lower relative risk for relapse in clozapine-treated groups, and studies with well reported random order generation according to Jadad criteria tended to have better odds ratios for clinical improvement on clozapine. These findings strengthen the evidence of true clozapine superiority in these aspects. No other quality items correlated to the primary outcomes. Inadequate randomisation techniques may be a source of bias in clozapine studies, but much more research is needed on the connections between trial quality and trial outcome.

Clozapine for Treatment of Schizophrenia-Reply

In Reply. —Dr Orr questions the use of a placebo period described in the selected patient who was reported in our article. This patient participated in a carefully controlled, prospective, double-blind treatment trial with the then-experimental and atypical antipsychotic clozapine. 1 This study resulted in the first non—industry-supported data indicating the superiority of clozapine in comparison with a representative traditional antipsychotic. Informed written consent was required prior to entry into the study; the patient's continuing assent and understanding of experimental procedures were monitored regularly throughout the study. Withdrawal of consent at any time and for any reason is justification for termination of participation. The inclusion of a placebo period in the crossover design enabled biological and clinical investigation into the effects of clozapine with minimal contamination by prior drug treatment. This approach led to a number of observations pertaining to the mechanism of action and clinical effectiveness of clozapine. 2,3

Restless legs syndrome

<h3>In Reply.</h3> —Dr Orr questions the use of a placebo period described in the selected patient who was reported in our article. This patient participated in a carefully controlled, prospective, double-blind treatment trial with the then-experimental and atypical antipsychotic clozapine.¹This study resulted in the first non—industry-supported data indicating the superiority of clozapine in comparison with a representative traditional antipsychotic. Informed written consent was required prior to entry into the study; the patient's continuing assent and understanding of experimental procedures were monitored regularly throughout the study. Withdrawal of consent at any time and for any reason is justification for termination of participation. The inclusion of a placebo period in the crossover design enabled biological and clinical investigation into the effects of clozapine with minimal contamination by prior drug treatment. This approach led to a number of observations pertaining to the mechanism of action and clinical effectiveness of clozapine.^2,3

Patient response and resource management: another view of clozapine treatment of schizophrenia

Issues in clozapine treatment were considered in terms of implications for resource management. A critical review of the literature on time course and pattern of response to clozapine was used to address treatment of negative symptoms, late responders, and extent of clinical benefit in ordinary settings. Superior efficacy of clozapine for partial and poor neuroleptic responders is observed in about one-half of the cases. Response is rapid once a therapeutic dose is reached, and the data do not support the proposition that some patients first respond only after 3-12 months of therapy. The cumulative benefit over several months of treatment and the broad range of symptoms involved in response are similar to those for typical neuroleptic drugs, suggesting that clozapine's superiority is based on greater effectiveness rather than a unique profile of treatment effects. Clozapine appears to be effective for secondary, but not primary, negative symptoms. Modal response is moderate, and extensive rehabilitation and clinical services are required to substantially enhance functional outcome. Many more patients merit trials with clozapine. Economic costs and adverse drug effects can be minimized by selecting patients most likely to benefit and discontinuing clozapine treatment when benefit is not observed within 2-4 months. Appropriate patients include 1) those with good responses to typical neuroleptics who experience substantial adverse effects and 2) those whose disorders respond poorly to standard neuroleptics and are defined by psychotic symptoms, thought disorder, and hostility. Treatment of primary negative symptoms is not supported by the current experimental data.