What Is the Place of Clozapine in the Treatment of Early Psychosis in Canada?

Abstract

Research and development of early intervention (EI) services for first-episode psychosis have brought much-needed transformation of service delivery for this serious mental disorder to many jurisdictions. The effectiveness of the EI model of service delivery is contingent on timely access to all evidence-informed treatment interventions, including a rational approach to pharmacotherapy. In this perspective paper, we present a brief review of the well-established effectiveness of clozapine in patients who clearly show lack of response to regular antipsychotic therapy. We concentrate, in particular, on the need to identify eligibility for clozapine therapy very early on following failure of treatment on 2 antipsychotic medications. We suggest that attention to the low use of clozapine in the very early phase of treatment of psychosis may be of particular value, as the response to clozapine at this stage is likely to produce larger benefits in other domains of outcomes because of the greater retention of patients’ personal and social agency.

The long-term trajectories for schizophrenia outcomes are established generally in the first 2 to 5 years following onset of symptoms and first exposure to treatment. ¹ As a result, this period has been referred to as “the critical period,” ² and any intervention likely to improve outcome could have its greatest impact during this period.

Over the past nearly 2 decades, burgeoning interest in the early phase of psychotic disorders (the critical period) has led to the creation of specialized early intervention (EI) services in many jurisdictions, such as Canada, the United Kingdom, and Australia. ^{3 –6} These EI services usually comprise comprehensive phase-specific medical and psychosocial interventions and attempt to reduce delays in treatment. ^7,8 In general, the impact of these EI services has been positive on clinical and social outcomes for most patients, ^6,9 with a higher proportion of patients experiencing remission of symptoms ^10,11 and achieving improved functional outcomes in EI services ^{6,10 –12} compared with other care models. A major source of benefit to patients comes from a higher level of engagement and adherence to the main components of treatment, such as antipsychotic (AP) medication, case management, and family intervention. This may be in part because younger patients in the early phase of psychosis often have more of their social, family, and personal resources intact.

Despite these benefits, a substantial proportion of patients will have 1 or more relapses during the first 5 years of illness, ^{13 –15} even with EI services, ¹⁵ and some individuals will see no benefit from such comprehensive treatment, because of a lack of response to AP medication. In the later phase, as well as in the literature on early-phase psychosis, if patients fail to reach remission of positive or negative symptoms, despite having tried at least 2 different AP medications, they are unlikely to achieve good functional outcomes ^11,16 or acquire a sense of personal recovery. ¹⁷

A large body of evidence suggests that patients failing to respond to 2 AP medications would meet criteria for “AP treatment resistance” (see the following discussion for details), irrespective of how long they have been in treatment. Most treatment guidelines would regard the use of clozapine in such situations as the obvious evidence-informed decision for clinicians to pursue (for example, the National Institute for Health and Care Excellence [NICE] guidelines ¹⁸ ). Unfortunately, there is a perception that the use of clozapine remains a treatment of last resort in early-phase psychosis, its use often limited to a much later and a more chronic stage of the illness. This may also be related to use of the term “treatment resistance,” which implies some degree of desperation, apart from the very stringent criteria applied to such a definition.

In this article we examine (1) the concept of AP treatment resistance as it applies to the early critical phase of illness, (2) the evidence for the use of clozapine in schizophrenia and related psychotic disorders in general and the application of this evidence to the early phase of psychosis, and (3) the problem of underuse of clozapine in this phase and reasons for such underuse in Canada. Finally, we offer some practical recommendations.

Treatment Resistance or Clozapine Eligibility?

Originally, Kane et al ¹⁹ defined resistance to treatment as (1) exposure to AP treatment with agents from at least 2 different chemical classes at doses equivalent to a daily dose of 1000 mg or more of chlorpromazine for a period of at least 6 weeks each without significant symptomatic relief and (2) no period of good functioning within the proceeding 5 years. Individuals had to have (1) a score of at least 45 on the Brief Psychiatric Rating Scale, with item scores of at least 4 (moderate) on 2 of the items conceptual disorganization, suspiciousness, hallucinations, or unusual thought content, and (2) a minimum Clinical Global Impression scale score of 4 (moderately ill). Although clearly this definition was tested and applied to patients with many years of illness, followed by later trials indicating the utility of clozapine even in cases of partial resistance, ²⁰ there have been some attempts at “softening” the criteria for definition of treatment resistance in terms of number, dosage, and duration of failed trials on AP medications and the severity and duration of illness required. ^{21 –23} For the earlier phase of illness, however, the definition of treatment resistance needs to be revised to address the fundamental issue of early identification of failure to respond to the regular AP medications. A recently suggested classification of schizophrenia on the basis of psychotic symptom response to AP medications attempts to change the terminology from “treatment resistance” to “clozapine eligibility” and proposes a shift away from focus on chronicity. ^23,24

Evidence to Support the Use of Clozapine in the Early Phase of Schizophrenia

Clozapine has been accepted as the gold-standard treatment for patients who meet criteria for treatment resistance. ^{18,25 –28} A meta-analysis of 12 controlled studies concluded that patients with treatment-resistant schizophrenia have greater reductions in symptoms when treated with clozapine compared with typical AP medications, whereas atypical AP medications other than clozapine did not have this effect. ²⁰ Many of the guidelines are based on additional randomized controlled trials, which have consistently demonstrated that clozapine is more effective in alleviating symptoms in patients with treatment-resistant schizophrenia compared with other atypical AP medications. ^{25 –28} The UK long-term effectiveness study CUtLASS 2 (Cost of Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) ²⁹ demonstrated that for patients failing to achieve a good response in 1 year on 2 AP trials, clozapine was more effective than switching to a third AP drug. Clinicians accept this as reflective of their own experience, although a recent meta-analysis of multiple AP medications has challenged the superiority of clozapine over other AP medications for treatment-resistant schizophrenia, primarily on the basis of the evidence derived from blinded randomized controlled trials. ³⁰ A critical examination of the methodological challenges that have influenced the conclusions of this meta-analysis is beyond the scope of this article.

It is understood clinically that some individuals with psychotic disorders may be inherently nonresponsive to AP medications, ³¹ whereas others, having initially responded to medication, may fail to do so later in the course of their illness following 1 or more relapses. A proportion of individuals in the early phase of psychosis may map to both descriptions. Both these groups may, however, benefit from treatment with clozapine.

Given the evidence to support the use of clozapine in patients not responding to 2 trials with AP medications, it is worth examining whether such use of clozapine would be even more beneficial early in the course of illness, as such treatment refractoriness is likely to be demonstrated relatively early. In a Canadian study, 244 patients diagnosed with first episodes of nonaffective psychosis ³² were initially treated with either risperidone or olanzapine for 6 weeks and showed good response rates of 66% of and 82%, respectively. Nonresponding patients were switched to the alternative medication, resulting in 9 of 35 patients’ responding to olanzapine (25%) and 1 of 25 (4%) responding to risperidone following the switch. The remaining 50 patients (20%) not responding to either drug were offered a trial of clozapine; 21 of the 28 who accepted responded (75%), compared with none of the 22 who remained on the previous AP medication. The results of this study suggest that treatment refractoriness to regular AP therapy can be identified and addressed relatively early in the course of treatment. In addition to the benefits on psychotic symptoms, there is evidence to suggest that clozapine is also effective in reducing suicidal ideation and behaviour, ³³ as well as craving for substances in cases of severe substance abuse. ³⁴ Both these problems are prevalent in the early phase of psychosis and affect several domains of outcomes, and effective pharmacotherapy is an important component in the integrated approach to these important issues.

Clozapine Use

In a recent review of evidence-based practices in mental health care, Horvitz-Lennon et al ³⁵ identified underuse of clozapine as among the most conspicuous examples of a lack of attention to evidence-based medicine. In Canada, fewer than 7% of patients with schizophrenia are using clozapine, ³⁶ whilst a New Zealand study ³⁷ reported that 917 of 2796 outpatients with schizophrenia (32.8%) were prescribed clozapine. The number of prior trials with AP medication ranged from 2 (37%) to 6 or more (12%), with a mean treatment duration before clozapine of 9.7 years. Only 18% and 19% had started clozapine in 2 years or less and 3 to 5 years, respectively, since initiation of AP therapy. Although the overall rate of use of clozapine appears very low in Canada, the rate of its use in the first 2 to 5 years following first treatment of a psychotic disorder remains unknown. An informal survey of early psychosis programs in Canada, conducted by the Canadian Consortium for Early Intervention in Psychosis, revealed a rate that is significantly lower than what would be suggested by the rate of failure of AP treatment.

Why then is the use of clozapine in early-phase psychosis so low in Canada? A number of possible reasons may explain this gross underuse. Patients may decline this treatment, or they may not be able to tolerate clozapine. Alternatively, as with depot AP medications, physician attitudes toward the use of clozapine may preclude its use. Here we examine these possibilities.

Clozapine, although it shows benefits in treatment-resistant patients, is limited by its side effects, the most serious of which is agranulocytosis, the risk for the latter necessitating regular blood monitoring. Although agranulocytosis is a serious and potentially life-threatening adverse effect with a rate of 3.8% to 8%, ^{38 –40} rigorous monitoring has apparently prevented any serious consequences, and mortality attributed to the condition is relatively low (case-fatality rate 2.2%-4.1%). ^40,41 Clozapine is more often associated with other side effects, such as sedation, weight gain, hypersalivation, constipation (gastrointestinal hypomotility), myocarditis, cardiomyopathy, and an increased risk for diabetes, ⁴² compared with other AP medications, except olanzapine. In fact, rate of diabetic ketoacidosis is lower than that of agranulocytosis (1.2%-3.1%), while case fatality from it is high (20%-31%). Furthermore, the case-fatality rate for gastrointestinal hypomotility is also high (15%-27.5%), with an incidence similar to that of agranulocytosis (4%-8%). ⁴³ It is quite likely that these potentially serious side effects and a need for very close monitoring for agranulocytosis act as barriers to higher use of clozapine in this phase of illness. It remains, however, unknown whether physicians are recommending this highly effective treatment to patients following absence of response to 2 AP medications and discussing with patients and their families the risk and benefits relatively early in treatment.

It is possible that there may be structural barriers, such as lack of support for psychiatrists to monitor patients on clozapine and the extra time required for care of patients requiring clozapine therapy. There may exist, in addition, some attitudinal bias on the part of physicians and other clinicians, who may regard clozapine therapy as an indication of chronicity and an “end state,” much like what has been reported for long-acting injectable AP medications. ⁴⁴ It also remains unclear if despite such efforts, patients and their families are reluctant to accept clozapine therapy and interventions that might improve their acceptance of a potentially lifesaving treatment, given its effectiveness not only for psychotic symptoms but for reducing suicidal behavior and craving for substances misuse. Are patients and their families able to weigh the benefits and risks of clozapine relatively early in the course of illness, while being assured of full attention to the potential side effects? Clearly there is still a major knowledge gap about the underlying reasons for lack of response to AP medications seen in a substantial minority of patients, even at the stage of being treated for their first episodes of illness. These questions need further exploration within early psychosis services in order to bring to the attention of clinicians and patients and their families how this treatment fits within the context of achieving better functional outcomes and a better chance for recovery.

Recommendations

Epidemiologic and clinical estimates of the prevalence of treatment resistance on the basis of lack of response to 2 AP medications suggest that 16% to 20% of patients with schizophrenia should be using clozapine. ^20,24,45 the rate likely to be similar during the first couple of years of treatment. In support of these figures, when clozapine treatment was implemented strictly in accordance with the UK-based NICE clinical guidelines for schizophrenia in a UK tertiary referral assertive outreach service, 24% of patients were taking clozapine. ⁴⁵ However, we recommend dealing with this issue on several fronts. The development of a comprehensive database from a large cohort of patients being treated for first-episode psychosis and followed throughout the critical period would assist in determining the proportion of patients who present with failure to respond to trials with 2 AP medications and, therefore, meet eligibility criteria to be offered clozapine. Furthermore, investigations of mechanisms underlying the lack of response to adequate trials of 2 AP medications following initiation of treatment of a first episode of psychosis are needed. There may be other markers of lack of response to AP medications. Poor verbal memory and reduced grey matter hippocampal volumes have been identified as possible candidates for failure to achieve early remission. ^46,47

Implementing evidence-informed treatment into the routine practice of clinicians remains a major challenge in mental health care, ⁴⁸ for both psychological (for example, cognitive behavioural therapy) as well as pharmacological interventions (for example, clozapine therapy). Indeed, reasons for gap between what we know works and what patients receive are very poorly understood. Implementation of highly effective treatments such as clozapine for a substantial subset of patients with psychotic disorders will require a better understanding of multiple barriers that often exist in scaling up an evidence-based treatment into clinical practice. Such barriers need to be examined within the framework of the emerging implementation science and include level of knowledge of practitioners, training required to achieve competence with using a treatment that may have some risks, and attitudes of practitioners toward the new treatment. ⁴⁹ Clinicians may also be reluctant to prescribe a medication that has been approved only for schizophrenia, under the assumption that diagnosis is likely to be protean during treatment of a first episode of psychosis. However, diagnosis of schizophrenia spectrum psychotic disorders is relatively stable across the first year, ⁵⁰ and patients not responding to regular use of AP medications are relatively easy to identify as meeting criteria for schizophrenia spectrum psychoses. Further studies on clozapine should concentrate on understanding its low use within the framework of implementation science in order to move forward, especially in the early phase of psychotic disorders. Early introduction of clozapine therapy is likely to be particularly feasible now in the context of the growing number of patients receiving treatment in EI services, in which monitoring is likely to be more intense and access to psychosocial interventions better. We continue to recommend the critical message to bring to patients’, families’, and clinicians’ attention that achieving and remaining in remission of symptoms is extremely important for engagement in and for deriving maximum benefit from highly effective psychosocial interventions such as cognitive remediation, family intervention, employment support programs, and stability in housing. These are all essential ingredients to moving from remission of symptoms to functional recovery.

Conclusion

Clozapine has a clearly established role in the management of treatment-resistant schizophrenia. How early in treatment clinicians should assess the eligibility of patients who do not respond to regular AP medications and then offer them this treatment has been addressed in several consensus treatment guidelines for schizophrenia from a wide range of prominent expert panels in Canada, the United States, the United Kingdom, Europe, and Australia. They all clearly recommend that clozapine be prescribed after adequate trials with 2 other AP medications, including an atypical agent, fail to produce an adequate response. ^{18,25 –28} NICE (https://www.nice.org.uk) has recommended that clozapine be introduced at the earliest opportunity once a patient has been diagnosed with treatment-resistant schizophrenia. Ensuring that patients are able to remit from symptoms and remain in remission will enhance their chances of benefitting from other psychosocial interventions and entering a phase of functional and personal recovery. However, the failure of implementation of this knowledge base in routine practice remains to be understood, and we recommend further investigations focusing on the application of implementation science to move forward.