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

  

    
CPG
    
Definition of TRS (when to start clozapine)
    
Management Algorithm
  
  

    
APA [14]
    
Persistence of Sx despite adequate Rx Tx: Total    duration of Sx of at least 12 weeks, of at least moderate severity, and    associated with at least moderate functional impairment as determined by    validated rating scales.

      or

      If a prospective medication trial of 2 APs at    least six weeks at adequate dose has not led to Sx reduction of more than    20%, and if the likelihood of substantial Sx improvement (e.g., >50%) is    small.
    
Clozapine with careful monitoring to minimize the    risk of harm*(1B)

      ↓ 

      Augmentation of clozapine with another AP/AD/MS, or

      Augment clozapine/other AP with ECT
  
  

    
BAP [15]
    
Failure to respond to 2 trials of AP medication,    of adequate dose and duration.
    
Clozapine is first-line Tx*(A)

      ↓ 

      Augmentation strategies with clozapine*(B), or

      Combined non-clozapine AP medications*(B), or

      Augmentation strategies with other classes of    medications*(B), or

      High-dose AP medication*(B)
  
  

    
CPA16
    
Two clearly identified adequate but failed AP    trials

      or

      Persistence of 2 or more positive Sx (less than 20%    reduction) of at least a moderate level of severity, or a single positive Sx    with severe or greater severity, following 2 or more adequate trials with    different AP medications.
    
Clozapine should be offered as first-line    treatment*(B)

      No consistent evidence to support the use of high    doses, switching, or combining AP medications
  
  

    
RANZCP17
    
Continued positive Sx after trials of at least 2    different APs at moderate doses (usually at least 300 mg of chlorpromazine    equivalents per day) for a reasonable period (usually at least 6 weeks).

      Tx-resistant disease should be recognized within    6-12 months of starting potentially effective AP Tx and confirmed as soon as    possible.
    
Clozapine is first-line Tx*(I)

      ↓ 

      If no response and/or side effects are severe, a    switch is suggested

      ↓ 

      When clozapine monotherapy is ineffective,    augmentation with other medicines or ECT*(III-1)
  
  

    
NICE18
    
Lack of satisfactory clinical improvement despite    the use of adequate doses of at least 2 different AP medications, including    an atypical AP, prescribed for adequate duration (at least 4 weeks each)

      or

      ‘Incomplete recovery’ defined as the presence of    lasting disability in functional and psychosocial aspects despite    psychological/psychosocial and Rx interventions, while also recognizing the    potential for improvement.
    
Clozapine is first-line Tx

      ↓ 

      If response to clozapine monotherapy is poor,    augmentation strategies are considered, or

      High-dose AP medication
  
  

    
SIGN19
    
Failure to respond to an adequate trial of 2    different AP medications, including a SGA.
    
Clozapine should be offered as first-line Tx*(B)

      ↓ 

      Clozapine augmentation with another AP*(C)

      ↓ 

      Clozapine augmentation with other medications*(B)a, or

      Switching to another AP, or

      High-dose AP medication*(D), or

      ECT*(C)
  
  

    
WFBSP20
    
A situation in which a significant improvement of    psychopathology and/or other target symptoms has not been demonstrated    despite Tx with 2 different AP medications from at least 2 different chemical    classes (at least one should be an atypical AP), at the recommended AP    dosages for a Tx period of at least 2–8 weeks per drug trial.
    
Clozapine is first-line Tx*(B)

      Switch to another SGA*(B), or

      Combination of clozapine with another SGA    (possibly risperidone)*(C), or

      AP combination therapy*(C), or

      Combination with other neuroactive drugsb:    AD, anxiolytics, etc.,

      or

      ECT*(D)
  
  

    
Legend: CPGs:    Clinical Practice Guidelines; APA: American Psychiatric Association; BAP: British    Association for Psychopharmacology; NICE: National Institute for Health and    Care Excellence; RANZCP: Royal Australian and New Zealand College of    Psychiatrists; CPA: Canadian Psychiatric Association; SIGN: Scottish    Intercollegiate Guidelines Network; WFSBP: World Federation of Societies of    Biological Psychiatry; Sx: Symptoms; Rx: Pharmacological; Tx: Treatment; AP: Antipsychotic;    AD: Antidepressant; MS: Mood Stabilizer; ECT: Electroconvulsant Therapy; SGA:    Second Generation Antipsychotics.

      *Level    of evidence or grade of recommendation, as per the specific clinical practice    guideline (described in Table 1); aThis level of evidence is only    reported in combination with lamotrigine; bDepending on the drug,    the level of evidence is varied from B to F.
  

Table 4: Definition and recommendations for the management of TRS in the schizophrenia CPGs.

Discussion

Relevant findings of this review of seven CPGs reveal that clozapine has strong evidence for important efficacy outcomes in schizophrenia, such as:

Reduction of mortality: No large, long-term, Randomized Controlled Trials (RCTs) have studied the effects of clozapine or of other antipsychotic medications on mortality. However, the results of two large pharmaco-epidemiological cohort studies have consistently shown that treatment with clozapine is associated with a reduction in all-cause mortality in patients with schizophrenia [23,24]. In one of these studies, the mortality rate also increased one year after clozapine discontinuation [24]. These findings are consistent with results of a recent meta-analysis where the mortality rate was reported to be significantly lower in patients who are continuously treated with clozapine as compared to those treated with other antipsychotics [25].

Decreased hospitalization: The hospitalization rate among patients with schizophrenia is high, regardless of the stage of the disease [26-28]. This may be due to relapse, non- compliance, or no response to treatment. Even though clozapine is usually started while patients are in hospital, studies have consistently shown that treatment with clozapine is associated with a reduction in hospitalization and re-hospitalization rates by 20-30%, especially when it is used in patients with suicidal or aggressive behavior [29-34]. Combination of clozapine with other antipsychotics, such as aripiprazole, has shown even better reduction in hospitalization rates when compared to clozapine alone [32,34].

Decreased relapse rate: There are a few head-to-head studies comparing different antipsychotic medications in relapse prevention. All Second-Generation Antipsychotics (SGAs) have shown superiority over First-Generation Antipsychotics (FGAs), and thus are recommended as first-line in all the schizophrenia guidelines reviewed [6,35,36]. However, CPGs do not recommend any particular SGA for relapse prevention. Clozapine and Long Acting Injectable Antipsychotics (LAIAPs) have been reported as having the highest relapse prevention rates [22]. Because LAIAPs are known to improve adherence in schizophrenia [37], some guidelines are recommending their use in combination with clozapine for relapse prevention [15,17].

Increased adherence: Non-adherence to treatment has been associated with negative patient outcomes, such as becoming aggressive, increased risk to self-harm and increased likelihood of substance misuse [38-40]. Thus, it has been suggested that the efficacy of clozapine in the management of patients with suicidal or aggressive behavior may be due to improved adherence while on clozapine treatment [33]. Both, APA and BAP guidelines provide several strategies for improving adherence in schizophrenia, such as the use of LAIAPs, regular contact with patients, or measuring the medication’s plasma concentration [14,15].

Cost-effectiveness: Results of the CUtLASS band 2 study, which compared clozapine with other SGA medications, clozapine showed to be more efficacious but resulted in higher treatment costs [41]. However, the NICE guideline attributes the higher costs possibly because, at the time when the study was conducted, patients needed to be hospitalized to start clozapine therapy [18]. As clozapine treatment can nowadays be initiated in an outpatient setting in most countries, there is a need for its cost-effectiveness to be re-examined, particularly in TRS. Overall, costs of clozapine treatment differ by country and geographic region, as well as in the payment models throughout different health systems [14,15].

Clozapine indications in people with schizophrenia

Management of TRS: All the schizophrenia CPGs reviewed provided strong supporting evidence on clozapine’s efficacy in the management of TRS and was recommended as the agent of first choice for this indication. The main difference among the CPGs was in relation to the definition of TRS, and on recommendations about when to start clozapine in the course of the disease. It has been suggested that variations in these definitions are the result of an inconsistent criteria used to include patients with TRS in clinical trials [4]. In addition, key aspects of determining treatment resistance, such as adherence to prior antipsychotic use, is not consistently assessed [10]. Another important difference in the recommendations provided in the schizophrenia CPGs is in regards to the treatment of choice for patients experiencing Clozapine Resistance (CR). The WFBSP and the RANZCP guidelines suggest switching to another SGA as monotherapy before considering augmentation strategies, while the other guidelines recommend augmentation with antipsychotic medications as the first step. These are mostly low-grade recommendations, as evidence from RCTs for the management of CR among TRS patients is limited and mostly supported by unpowered studies [32,42]. Some CPGs recommend to consider combination with medications with a complementary receptor profile to clozapine, but with a different safety profile [14,15].

The last treatment option for patients with TRS recommended in the CPGs reviewed is the use of Electroconvulsant Therapy (ECT) alone or as adjuvant. Although there are limited number of studies on the use of ECT in TRS, the results are generally positive in terms of safety and efficacy [43,44]. ECT has shown to reduce the rate of relapse in TRS when added to clozapine. However, this is only reported for patients who showed benefit from ECT before meeting the criteria for TRS [45]. A recent international initiative of experts in the field of schizophrenia developed consensus recommendations for the management of CR TRS patients [34]. Raising clozapine plasma levels to ≥350 ng/ml for CR patients with positive, negative, and mixed symptoms was recommended. For CR patients with mostly positive symptoms, combination with a SGA (such as amisulpride or oral aripiprazole), and augmentation with ECT or with a moodstabilizer or with another antipsychotic medication (particularly for TRS patients with CR aggressive symptoms) were recommended. For CR patients with predominant negative symptoms, augmentation with an antidepressant or with a mood-stabilizer (particularly for TRS patients with CR suicidality) and ECT were recommended [34].

Other indications: Other schizophrenia-related indications for clozapine that were generally supported with relatively high levels of evidence in the CPGs was the management of aggressive behavior and of suicidal risk. Numerous studies have demonstrated the superiority of clozapine over other antipsychotic medications in reducing the rates of self-harm, suicidal attempts, and suicidal mortality [24,46-48]. The anti-hostility effect of clozapine has also consistently been demonstrated in several studies regardless of any symptom improvement (positive or negative) [30,33,49].

The WFSBP was the only guideline that provided supportive evidence for the use of clozapine in first episode psychosis (FEP) [20]. Recent studies have shown significant higher rates of remission and lower rates of re-hospitalization in treatment naïve patients who treated with clozapine compared to those who were given different antipsychotics [50-53]. Studies have also shown a response rate of 75-80% when clozapine was initiated early in the treatment of schizophrenia [54]. However, most CPGs do not recommend initiating clozapine for FEP primarily due to safety concerns, particularly its hematological risk profile [14,15,17,20]. In addition, concerns about a higher incidence of adverse effects in younger patients (who are likely those experiencing FEP) have been reported [55,56]. Only the WFSBP and SIGN guidelines provide general statements on the efficacy of clozapine in treating primary negative symptoms [19,20]. No studies were found on clozapine’s efficacy on primary negative symptoms compared to placebo. Although studies have shown that clozapine is effective for the treatment of negative symptoms when compared to FGA and some SGAs, in trials that lasted longer than 3 months, the efficacy of FGA on negative symptoms was not significantly different than when using SGAs [30,33,57-63]. In general, based on the recommendation provided in the CPGs reviewed, there is no pharmacological treatment for the management of primary negative symptoms. Further studies are needed to address the specific role of clozapine in this indication.

Clozapine’s safety profile

Our review identified that overall CPGs provided limited information about certain aspects of clozapine’s safety profile and monitoring recommendations. Agranulocytosis is the most serious, but rare, side effect of clozapine, but its incidence has significantly been reduced from 1-2% (when first reported) to 0.9% [64]. This was mostly achieved because of the mandatory hematological monitoring that is required for all patients during the first year of clozapine treatment [65,66]. Although all the CPGs promote adherence to the monitoring requirements in order to ensure positive efficacy and safety outcomes in patients with TRS, there are discrepancies in regards to the required hematological monitoring among all the CPGs. Some guidelines are very prescriptive, for example, the APA requires that clozapine prescribers register under the Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) program, which requires weekly hematological monitoring from initiation to 6 months, followed by every 2 weeks from 6 to 12 months [14], while the NICE guideline only recommends routine monitoring without being too prescriptive [18]. Considering that this particular safety aspect of clozapine is associated to clinicians preferring the use of less effective treatment options [67], it is important that consensus among the different CPGs is established in regards to the optimal (and safest) frequency of hematological monitoring. Another aspect of limited information on all the CPGs is in relation to clozapine’s interactions with smoking. Only APA, NICE, and RANZCP guidelines describe the effect of smoking on clozapine metabolism and how to manage schizophrenia treatment among smokers [14,17,18]. Smoking induces the main enzyme system responsible for the metabolism of clozapine (particularly CYP 1A2), leading to a potential reduction of clozapine plasma levels by up to 50% [68-70]. Therefore, higher doses of clozapine are required to achieve the therapeutic plasma levels in smokers. However, the majority of the schizophrenia CPGs do not sufficiently address this interaction in the smoker population. Recommendations, such as offering patient smoking cessation therapies, dose adjustments and monitoring of clozapine plasma levels, to minimize the potential decreased efficacy of clozapine among smokers, need to be consistently provided in CPGs.

Conclusions and Recommendations

A total of seven schizophrenia CPGs were identified in this systematic review of the literature, and vary in the scope of information presented. Numerous recommendations were consistently provided across all the CPGs reviewed, which would assist in clinical decision making when treating patients experiencing TRS, including:

• Clozapine remains the first treatment option with the strongest supportive evidence.

• Clozapine monotherapy is preferred. There is lack of evidence in support of antipsychotic polypharmacy.

• The evidence for augmentation of medications for clozapine refractory (CR) patients is limited, and mostly supported by unpowered studies.

This study also helped to identify some gaps in our knowledge about TRS treatment. Main differences in the recommendations provided were in relation to the definition of TRS, on the management of TRS patients who do not respond to clozapine treatment, on the breath of information in relation to clozapine’s safety profile, and on the frequency of hematological monitoring, that is required during clozapine treatment.

Future iterations of CPGs should seek consensus on certain aspects of TRS, particularly in regards to a clear definition of TRS and standardized measurements of response to treatment. As the safety profile of clozapine appears to be the main limiting factor for starting clozapine, CPGs should also provide support and advice on strategies to address them, such as implementation of clozapine clinics, multidisciplinary team involvement, and smoking cessation programs.

Declaration

Acknowledgements: We extend our thanks to the students in the Doctor in Pharmacy program at College of Pharmacy, Qatar University, who through their clinical rotations in mental health practice contributed to the literature review.

Author contributions: MZ contributed to the conception, design, and research protocol, in addition to being involved in all aspects of data analysis and manuscript revisions for intellectual content MN contributed to data collection, data analysis, and preparation of the manuscript. YE and OA contributed to the data collection process and critically revising the manuscript.

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