Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide

Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.


Authors' experience
This guide is based upon the authors' experience since 2006 of treating patients with clozapine following neutropenia in a UK high secure forensic hospital. This patient group presented combinations of treatment resistant schizophrenia, severe behavioural disturbances requiring the use of extended seclusion in addition to contraindications to the use of clozapine secondary to clozapine induced or other neutropenias. Given the lack of effective alternatives and the unacceptable clinical condition of the patients we began to re/use clozapine with an evolving approach to risk assessment, monitoring and mitigation. The results were very much better than expected. Clozapine was re/introduced to 14 patients despite neutropenia due to a variety of aetiologies; benign ethnic neutropenia (BEN), neutropenias secondary to both clozapine and other drugs and autoimmune neutropenia. Despite previous prolonged periods of detention in conditions of high security, half of our group improved sufficiently to transfer out of high security. There were significant reductions in the use of seclusion and there were no serious adverse events.

General warning
Any team considering clozapine in a patient with previous blood dyscrasia should proceed with great caution. All approaches are hazardous. The existing best evidence is derived from a small number of nationwide pharmacovigilance studies reporting crude outcomes on clozapine rechallenge in combination with individual case reports and series that will inevitably be affected by publication bias. These have been subject to meta-analysis [1]. The evidence relating to the use of drugs to support neutrophil counts is derived from case reports and series only. Decision making is entirely based on the individual circumstances of the patient, in the absence of any agreed protocols and with uncertainty regarding risks. Despite shared decision making having some advantages, we have found it helpful for responsibility regarding final decisions resting clearly with the consultant psychiatrist prescribing clozapine. Although treatment and mitigation planning itself is an extremely useful process, the plans developed will invariably have to be modified in the light of the patient's response and local team and resources issues; changes to treatment and neutropenia management is often required quickly. It is very helpful to acknowledge this in the plan itself. We have also had experience of the use of enforced naso-gastric clozapine [2] and with clozapine given after severe physical health comorbidities [3]; whilst clear and informed clinical decision making is essential, careful thought must also be given to the team and institutional factors that can facilitate or interfere with these sorts of intrusive and unusual interventions [4].

Clozapine and neutropenia
Clozapine continues to have unique efficacy in treatment resistant schizophrenia but remains a third line treatment on account of the increased risks of neutropenia and agranulocytosis [5,6]. Whilst the initial indications arose from a series of deaths in Finland [7,8] the subsequent risk monitoring and management regulations have resulted in deaths from these adverse effects being extremely rare. The rates of clozapine induced neutropenia (CIN) and agranulocytosis (CIA) are 3.8 and 0.9% but the incidence of death secondary to these complications, as managed by the monitoring arrangements, is 0.013 and 2.1% respectively [9]. The UK national pharmacovigilance has identified eight clozapine related blood dyscrasia deaths to date [10]. International regulations for clozapine monitoring vary [11]. The UK clozapine blood monitoring requirements are summarised in Table 1. In the UK, clozapine may only be used within licence as a third line treatment if there is no previous history of neutropenia from any cause and with blood monitoring.
Neutrophil counts are categorised according to a colour-coded system [10]; if a patient has an Absolute Neutrophil count (ANC) < 1.5 × 10 9 /L (red alert) clozapine treatment must be stopped immediately. A lower threshold is available for patients with a heamatologicaly confirmed diagnosis of Benign Ethnic Neutropenia (BEN). The UK requirements have not yet aligned to use the lower neutrophil thresholds now used in the United States [12]. Afternoon blood sampling may optimise clozapine blood testing, ideally after exercise; this alone has been demonstrated to be sufficient to improve outcomes [13]. CIN and CIA are idiosyncratic, unpredictable type B adverse drug reactions [14,15]. The hypothesis of an immune mediated mechanism is supported by the timing of initial adverse effects and the tendency to have faster and more severe problems on rechallenge [16]. Genetic linkage studies suggest both immune and anion transporter gene related mechanisms [17][18][19][20] but are not sufficiently predictive to be clinically useful [21]. The metabolites of clozapine may be toxic to neutrophils [22].

Clozapine Rechallenge after CIN and CIA
The best available evidence regarding repeat dyscrasias with clozapine is conflicting. A 2006 publication of all available clozapine rechallenges in the UK and Ireland found the majority did not experience a repeat dyscrasia: 38% of patients (n = 20) experienced a repeat dyscrasia with a significant increase in severity, duration and speed of onset. However there were no deaths; all repeat dyscrasias resolved when clozapine was discontinued. The majority of dyscrasias occurred within 18 weeks of clozapine treatment; four occurred after this [23]. In 2016 data from a nationwide pharmacovigilance study in Argentina presented the outcomes of 19 patients rechallenged with clozapine; approximately one third of patients experienced a second dyscrasia which mostly occurred sooner during treatment but were less severe and of shorter duration [24]. Evidence from case reports shows a positive outcome in more than 60% of clozapine rechallenges after neutropenia (128 positive outcomes from 203 cases); there is less reported success following agranulocytosis (3 positive outcomes from 17 cases) [1].

Risk-benefit analysis
The risk-benefit analysis includes the likely benefit in terms of reduction of psychiatric morbidity following the use of clozapine balanced against the risks of a repeat dyscrasia, the risks of death or other adverse outcome secondary to a dyscrasia and the possible harms from the risk mitigation strategies used. Precisely define the current indication for clozapine and the supporting evidence. If clozapine has been used previously, was the clinical response sufficient to justify a rechallenge? If insufficient, were there problems related to the duration or dose / level achieved? If clozapine was previously discontinued, then is the response to the current treatment inadequate? Alternatives may have been attempted, although these are highly unlikely to be effective [25]. Given the risk and uncertainty of clozapine rechallenge and advice against the routine use of lithium or Granulocyte Colony Stimulating Factor (G-CSF) [26], the severity of the patient's condition should be at least severe if not extreme [27]. Very significant resistant psychotic symptoms should contribute to markedly impaired function, prolonged detention or serious risk to self or others. 2. Likelihood of benefit from clozapine: Patients who either had a previous good response to clozapine then dramatic deteriorations on withdrawal or who have never had clozapine present the groups most likely to benefit. Clozapine naïve patients have an approximately 33-40% chance of significant improvement [28,29]. Patients who have had limited previous clinical improvement with clozapine present uncertainties; some will have had partial responses and the records may not allow a full assessment. Most who make a good response to clozapine, as with other antipsychotics [30] do so relatively quickly, with noticeable improvements within weeks of initiation. An adequate trial of clozapine should consist of at least 8 weeks of therapy with plasma trough level above 350-400 mcg/L; some young men, particularly smokers, may require doses in excess of 900 mg/d to achieve this [31]. However, some may respond much later in treatment, although frequently sub-optimally, but even a small improvement may be sufficient to improve quality of life and function in groups as severely affected and restricted as ours [32,33]. In these cases there may remain the possibility of sufficient improvement to achieve management of violence [34] and or discontinuation of seclusion [2] if not full symptom control. Rechallenge should not be discounted in cases where the previous response was less than good, relatively brief or when plasma levels indicate room for dose escalation [31,33,35]; however, there will be increased uncertainty. Patients who discontinued clozapine after lengthy periods at substantial doses with higher than usual plasma levels without a response resulting in significant clinical improvements should not be rechallenged.
Risk assessment and information gathering 1. Is clozapine really prohibited?
The UK license for clozapine has changed. Some will have had clozapine withdrawn on a single red result only, with unrecognized Benign Ethnic Neutropenia (BEN) [36]or on the basis of one or more "amber" results. A search for the contemporaneous notes may be required in addition to liaison with the previous clozapine provider. Resolving  Paradoxically, restarting clozapine for some of our patients brought both potential risks and benefits to their mental states on account of clozapine withdrawal rebound psychoses even more extreme than their baseline [41]. This lends more weight to a more assertive approach to supporting neutrophil counts as well as enforcing clozapine [42] to avoid the most extreme disturbances.

Attempt risk stratification for repeat dyscrasia
Making a determination of the relative risk of a blood dyscrasia will help determine which strategy to use

Conclusions
A stratified approach to clozapine rechallenge after CIN / CIA and initiation after other neutropenias

Clozapine alone
There are a number of circumstances in which clozapine alone might be used in the face of previous reports of neutropenia: a. The simplest cases: misreported 'red alerts' either unconfirmed or not below threshold for previously undiagnosed BEN allow registration and use of clozapine within license without additional safeguards. b. Neutropenia due to other drugs historical or ongoing: if stopping another implicated drug results in a rapid increase in neutrophil count then there is a good case to be made to initiate clozapine with an off-license agreement. A team may wish to have a contingency plan in the event of a further episode of neutropenia. The contingency plan should reflect the severity of the patient's dyscrasia and psychosis. c. Low pre-treatment neutrophil counts with or without BEN: optimise blood sampling. Changing sampling time from morning to afternoon (ideally after exercise) may be sufficient to allow initiation and on-going treatment [44][45][46][47]. Longer-term processes are necessary to ensure this continues. Alternatively, following consultation with the clozapine monitoring service and a haematologist alongside an assessment of the risk of clozapine withdrawal and the degree of patient compliance, arrangements can be made for accepting lower neutrophil count thresholds before clozapine must be stopped: 1.0 × 10 9 /L or lower. In the United States these thresholds have recently been lowered [12]. In an oncology setting, action is not taken for absolute neutrophil counts below 0.5 × 10 9 /L unless there is evidence of infection [48]; however, in the mental health setting, risks are associated with this approach since patient cooperation may be minimal and the difficulties of managing an uncooperative physically sick patient extreme. d. BEN with treatment emergent recurrent subthreshold neutrophil counts without neutropenia: an advantage of the neutrophil monitoring requirements is that they include a large margin of safety. A disadvantage is that for some patients with BEN there may be repeated sub-threshold results (ANC between 1.0-1.5 × 10 9 /L) without sepsis and a requirement for multiple blood testing. If a patient will cooperate with this then there is no difficulty. It may be necessary to consider an agreement to continue to use clozapine but continue sampling at weekly or fortnightly intervals if the patient presentation justifies this. Identification of the Duffy Null genotype (the CC genotype of the rs2814778 variant of ACKR1) in those with African ancestry shows a robust association with low neutrophil counts and is thought to be the cause of BEN, thus allowing a more definitive diagnosis rather than the current "diagnosis of exclusion". This population has a more than 20 times increased risk of neutropenia on clozapine, most often as a result of BEN rather than an adverse drug reaction [20].

Drug treatments to support neutrophil counts
If neutrophil counts cannot be sustained at adequate levels, the use of lithium or Granulocyte Colony Stimulating Factor (G-CSF) can be considered if the risk of a dyscrasia and managing a rebound psychosis is considered too great. Tables 2 and 3 outline the use of G-CSF and Lithium. Our approach has evolved. Our first case involved a patient who had had multiple episodes of non-clozapine drug included neutropenia with sepsis, CIN with severe clozapine withdrawal psychosis and prolonged hospitalization, extensive violence, self-harm and extremely long seclusion; prior  [49][50][51], drug induced neutropenia [52].
Common adverse effects and management Flu like symptoms, bone pain, headache, pyrexia and fatigue.
Side effect management and monitoring Analgesia, monitoring for splenomegaly [68] and bone mineral density assessment [69].
Long term safety Available from the 20,000 annual healthy volunteer peripheral blood donors. Initial concerns of increased leukaemia risk alleviated by long term follow up [70]. to clozapine withdrawal there had been an excellent clinical response. The risks of rechallenge were high; the haematology advice favoured G-CSF over lithium to be used from the outset. In less extreme cases lithium can be a useful first line as set out by Manu [72].
a. BEN followed by treatment emergent CIN: Lithium or G-CSF can be used to support neutrophil counts depending on the severity of the neutropenia and the patient's history when psychotic. Lithium or G-CSF may be used to continue clozapine treatment [53,76,77]. Lithium or G-CSF can be given without interruption of clozapine treatment. Decision making will balance the risks of clozapine withdrawal against those of a dyscrasia and the likely benefit of the strategy used. The initial approach we used for one patient, with the assistance of a haematologist, was to give G-CSF as required (plus-rescue). After each dose of G-CSF there was an excellent response in neutrophil count; however, after eight episodes of neutropenia with a nadir of 0.4 × 10 9 /L the patient was established on regular G-CSF. Although clozapine naïve, this patient had had several episodes of life threatening self-harm and of serious assaults on others in the context of active psychosis. b. CIN with gradual deterioration on clozapine withdrawal, disturbed behaviour (not the most extreme): Lithium appears to have a good record of success when used to support clozapine rechallenge and has fewer difficulties in terms of side effects, administration, cost and downstream issues. There is little evidence regarding dose but in our experience a serum level of greater than 0.4 mmol/L has been sufficient to have a meaningful effect on neutrophil counts. This is easily assessed for each individual patient. If required, lithium can be replaced with G-CSF. These approaches were all successful in our patient group.
c. CIN with rapid deterioration on clozapine withdrawal, disturbed behavior (extreme): These patients present by far the most extreme problems in terms of the severity of neutropenia and psychosis. We have used prophylactic G-CSF in this group, with haematology assessment and support regarding dose, interval and monitoring.

For all cases
a. Avoid other implicated drugs. For all patients we avoid the use of any other drugs implicated in neutropenia. This is most relevant if there is a history of clozapine induced seizures or if affective symptoms are prominent in which case topiramate [78] may be preferable to valproate, lamotrigine or carbamazepine. b. Planning and Liaison. Careful teamwork will be required. A variety of simple practical steps were taken to ensure that G-CSF was available on the wards where it might be needed, with simple plans for its use should this be required by on-call junior medical staff. Whilst we increased the frequency of FBC testing (arbitrarily to initially twice weekly) plans were made to ensure that this was optimized in the afternoons, but not so late that results only became available out of hours. Liaison with other medical professionals can sometimes be confused with attempts to diffuse responsibility. It will be the treating psychiatrist who is responsible for the decision-making and not the haematologist. On occasion haematologists report requests from psychiatrists asking whether or not clozapine should or should not be restarted, rather than to advise on the hematological risks and how these might be managed. For cases when capacity is impaired or when patients do not consent, the difficulties and uncertainties must be shared with the legal power authorising treatment. The use of medication to support rechallenge may need to be specified depending on the approach taken by the approving body. In all cases, off-license agreements will be required with the clozapine provider. Family liaison will be important. In several of our cases both patients and their families, recognizing the benefits when clozapine had been used previously and the severity of the deterioration when it was withdrawn, were eager to rechallenge. c. Retitration rates. Given the probable contribution of an immune mechanism, a slower clozapine titration may be useful; as yet there is no evidence to support this [79]. d. How long to continue Lithium or G-CSF. This is not known.

Table 3 Lithium and Neutrophils
Physiological effects Enhances production of endogenous G-CSF, directly stimulating differentiation of stem cells and protecting neutrophils from the toxicity of some drugs, although to a far smaller extent than G-CSF.

Adverse effects in clozapine rechallenge
Isolated case reports of failure / fatality [74] and of neurotoxicity [75] Use, dose, side effects Familiar to psychiatrists Institutional / systemic factors Systemic difficulties not likley e. Timing. Clozapine rechallenge is anxiety provoking. Given the types of judgments required, we planned our blood sampling regimes to avoid results out of hours or when key decision makers were away from the hospital.

Downstream
Many of our patients rechallenged with clozapine have had an excellent clinical response; significant numbers have now been transferred to conditions of lesser security. This creates a difficulty. Novel, expensive and high risk treatment strategies may not be endorsed at future placements. Several of our patients have had changes to treatment regimes in downstream settings. These have not been problematic.