File no.: 1057-2019-2670-I-P Expiry: April 30, 2022

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Jamie Kellar, BScHK, BScPhm, PharmD, PhD(c)

Wende Wood, RPh, BA, BSP, MEd

The subject matter expert and expert reviewer have no conflicts of interest to disclose.

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Clozapine requires significant monitoring and clinician involvement to maximize patient outcomes and safety. However, the logistics around the use of clozapine can cause concern for both patients and clinicians.

This three module course provides pharmacists with important information regarding the use of clozapine for treatment resistant schizophrenia (TRS), as well as strategies to manage patients taking clozapine. These modules will provide key details, including:

A brief historical overview of clozapine from development to market

Information on clozapine’s unique pharmacology and effectiveness for TRS

Practical information on registering and monitoring patients

A detailed review of side effects

Practical tips for both pharmacological and non-pharmacological management of side effects

Monitoring strategies for efficacy and safety

Key points related to clozapine use and COVID-19

After successful completion of this module, you will be better able to:

Describe the role of clozapine in managing treatment-resistant schizophrenia

Explain what makes clozapine unique clinically and pharmacologically

Identify factors to consider when choosing clozapine for patients

Discuss approaches to building rapport with patients being treated with clozapine

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Clozapine was the antipsychotic that revolutionized the treatment of schizophrenia.

Clozapine was first synthesized in 1958.1,2 It was clinically unique, as it did not cause extrapyramidal symptoms (EPS) at therapeutic doses. This finding challenged widely held paradigms at the time that EPS was required for therapeutic antipsychotic effect.1,2 It is this lack of EPS that garnered clozapine the title of the first “atypical” antipsychotic medication. In addition to not causing EPS, clozapine may actually improve this side effect in patients who develop EPS secondary to other antipsychotic medication.

Clozapine was first marketed in 1972 in Switzerland and Austria. However, within several years (1975), it was withdrawn from numerous countries, including Canada, due to its association with a cluster of unexplained deaths, later determined to be related to drug-induced agranulocytosis.1,3

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In the late 1980s, a landmark trial established clozapine as superior to conventional antipsychotics for treating refractory schizophrenia.5 This trial established a niche for clozapine in treatment-resistant schizophrenia (TRS) and enabled its return to the market.1,3

Clozapine was re-introduced into the Canadian market in 19914 for the treatment of TRS, this time with the added requirement of routine blood monitoring.1,3

Clozapine is the gold standard for treatment-resistant schizophrenia (TRS). It should be offered to all patients with TRS and considered for patients who have not responded to two antipsychotics.6 Although this recommendation from the Canadian schizophrenia guidelines seems clear, defining TRS has not been straightforward, particularly in terms of what is considered an adequate treatment duration before an antipsychotic is deemed ineffective.7

Recently, the Treatment Response and Resistance in Psychosis (TRRIP) working group established consensus guidelines to standardize the definition of treatment resistance.7 Its definition includes a measurement-based absolute threshold symptom domain severity for at least 12 weeks with evidence of a measured, moderate functional impairment after two failed adequate therapeutic defined doses of antipsychotics for a minimum duration of six weeks each.7

All of the current guidelines for the treatment of schizophrenia acknowledge the superiority of clozapine in managing TRS and treating residual symptoms, persistent violent behaviours, tardive dyskinesia and suicidal thoughts or behaviours.6,8,9,10,11,12,13,14

Despite robust evidence for clozapine’s efficacy in TRS, some individuals may not have a therapeutic response to clozapine. Even with optimum clozapine treatment, only 30%-60% of patients with TRS will respond satisfactorily.6,7,11 This leaves a significant number of

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patients with TRS who require additional measures to achieve optimum therapeutic benefits. Often, treating these patients with clozapine plus another antipsychotic, such as risperidone or aripiprazole, or an anticonvulsant such as lamotrigine, is tried.15,16,17,18,19,20,21

The duration of a trial of clozapine to assess efficacy in individuals with TRS has also been debated, and there is no clear consensus. In general, it is recommended that patients should be kept on a therapeutic dose of clozapine for a minimum of eight weeks, assuming they are tolerating the medication.20 Note that clozapine is both the gold standard and the “last resort” in the treatment of TRS. Numerous studies have looked at duration of clozapine trials, and many describe patient improvement for up to 12 months, with quality-of-life and cognitive improvements occurring only after six months of treatment.20

The evidence to support augmentation of clozapine with a second antipsychotic or an anticonvulsant is modest at best.15,16 Some trials indicate some improvement in symptoms with augmentation, yet others have found no difference.16,18,19 In the absence of robust studies, clinicians will often try augmentation strategies for individual patients, weighing risks and benefits and assessing symptoms on an ongoing basis.

Pharmacy practice tip:

Pharmacists are ideally placed to monitor the efficacy and side effects of the augmenting agent due to frequent dispensing which creates opportunities for follow up. If the augmenting agent does not improve symptoms or causes significant side effects pharmacists can recommend the agent be discontinued. Reducing polypharmacy in individuals with TRS is important for improving quality of life.

In general, most patients should be titrated to a minimum dose of 300 mg daily, with titration up to 900 mg daily maximum where required, based on the individual patient’s needs. Therapeutic drug monitoring (TDM) can also be used to guide clozapine dosing; however, the reference ranges vary. In general, there are data suggesting that a minimum plasma trough level of 350 μg/L is necessary for efficacy.20

To monitor trough levels of clozapine, blood levels are usually drawn 12 hours after the last dose, which is generally the morning after the nighttime dose. In patients with trough levels above 400 μg/L, doses are usually titrated to patient tolerability. Blood level monitoring is not required to guide dosing. The use of blood monitoring is variable and is predominantly dependent on prescriber preference.

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Mr. Adams is a long-time patient of your community pharmacy. He lives in a group home for which your pharmacy provides medication services. Today you are at the group home conducting medication reviews for several patients, including Mr. Adams. He is 41 years old and has schizophrenia and type 2 diabetes. He also has gastroesophageal reflux disease (GERD). He smokes approximately one pack of cigarettes per day, does not drink alcohol, and does not use any illicit substances. Mr. Adams is currently taking quetiapine 800 mg po qhs, metformin 1000 mg po bid, pantoprazole po 40 mg daily, and lorazepam 1 mg po qhs prn.

As you review his history, you notice that Mr. Adams continues to have significant symptoms of schizophrenia, including hearing voices, and experiencing delusions of grandeur (he thinks he is the King of England), and a lack of motivation. He has tried several antipsychotics, including haloperidol 10 mg po qhs, perphenazine 16 mg po bid, olanzapine 30 mg po qhs, aripiprazole 30 mg po daily, and risperidone 6 mg po qhs. He has been on each of these treatments for several months to years, with no clear improvements. There is a note in his profile indicating that he had significant EPS with haloperidol.

This is a good next step. Based on your review, it appears that Mr. Adams meets the criteria for TRS, and he has never taken clozapine. Lab technicians regularly visit the group home, so he will be able to comply with the requirement for lab work.

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Based on Mr. Adam’s history, it is unlikely that a dose increase would improve his symptoms. He is currently on the maximum recommended dose of quetiapine; hence, there is likely to be little improvement with a higher dose. If Mr. Adams has TRS, the data supports clozapine having superior efficacy over all other antipsychotic agents. Instead of recommending an increase in the quetiapine dose, consider discussing the possibility of a clozapine trial.

Mr. Adams’ lack of response to prior medications suggests TRS; so, there is a solid case to advocate for the initiation of clozapine. The prescriber may not have a robust medication history, and you may be able to provide crucial information to support a change in diagnosis to TRS and thus a trial of clozapine.

In addition to being clinically unique, clozapine is also pharmacologically unique. In general, antipsychotic activity is attributed to antagonism (blockade) of the D2 receptor. Most antipsychotics have high affinity for D2 receptors throughout the brain, and it is their D2 antagonistic activity in the mesolimbic pathway that is associated with reducing the positive symptoms of schizophrenia, and the D2 antagonistic activity in the nigrostriatal pathway that leads to EPS. In contrast, clozapine has low affinity for the D2 receptors, thus suggesting its efficacy is associated with activity other than D2 receptor affinity and occupancy.2 This low D2 affinity also partially explains the absence of EPS. Table 1 shows the receptor affinity of clozapine.

Dopamine D4 D1 D2, D3

Serotonin 5-HT1C, 5-HT2 5-HT3

Noradrenaline α1 α2

Acetylcholine Muscarinic

Histamine H1

In addition to low D2 affinity, clozapine has high affinity for other receptors including the D4 receptor, serotonin receptors (5-HT2A, 5-HT1C), and adrenergic and cholinergic receptors.

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The exact role of the D4 receptor is not clear; however, it is postulated that clozapine’s D4-blocking activity is associated with improved negative and cognitive symptoms.

Studies have suggested that because of its unique pharmacology, clozapine may be superior to other SGAs in controlling positive symptoms that are not responsive to conventional FGAs in patients with chronic schizophrenia.12,13 Evidence from a systematic review and meta-analysis suggests that clozapine may also be more effective than other antipsychotics for managing negative symptoms (e.g., apathy, social withdrawal) in the short term, but not in the long term.13

Other benefits with clozapine have been demonstrated, including:

Improvement in cognitive function23,24

Reduction in suicidality25,26

Relief of caregiver burden27

Possibly, less need for adjunctive medications28,29

There is also relatively strong evidence for anti-hostility and anti-aggression effects with the use of clozapine independent of its overall efficacy or minimization of adverse effects such as akathisia.30,31,32

Clozapine is generally reserved for patients with TRS and thus is not a first-line agent. Before initiating therapy, several factors, as outlined below, must be considered.

The patient (or substitute decision maker) must consent to treatment with clozapine. This can be difficult as patients, especially those with specific needle phobias, are often concerned about the frequency of the bloodwork.

The patient is willing/able to meet routine blood monitoring requirements.

The patient has had previous inadequate response to antipsychotic treatment (usually has failed a minimum of two different antipsychotic agents).

The patient can access clozapine (i.e., available in the patient’s pharmacy, covered by a drug plan, or patient can afford to pay; prescriber available to order and monitor, etc.).

The patient has no contraindications to the medication (i.e., non-rechallengeable status).

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The patient has undergone a full medical assessment, including baseline laboratory tests (e.g., liver function tests, complete blood count with differential, fasting blood sugar, A1C, cholesterol), ECG, CRP, troponin, and a physical exam (i.e., weight, blood pressure, waist circumference).

A complete review of patient’s current and past medical conditions, including family history, should be obtained and documented.

A thorough list of the patient’s current medications, including prescription medications, non-prescription agents including natural health products and vitamins, and substances of abuse should be documented. Obtaining a full and comprehensive list is imperative, as clozapine has the potential for many significant drug interactions.

Smoking increases clozapine metabolism due to CYP 1A2 induction; thus, clinicians should know how much patients are smoking (i.e., number of cigarettes/day) and should note any significant changes to smoking patterns during treatment. All patients should be actively encouraged and supported to quit smoking, since large changes in a patient’s smoking can impact clozapine blood levels and result in changes in efficacy and/or adverse effects.

Pharmacy Practice Tip

Clozapine has the potential to interact with numerous medications. There are pharmacokinetic interactions like the smoking example above, which are mediated through CYP enzymes. There are also pharmacodynamics interactions such as increased sedation when clozapine is combined with medications such as benzodiazepines. Most drug interactions are not clear contraindications, however all medications that a patient is on should be explored for potential interactions with clozapine so clear efficacy and side effect monitoring plans can be created.

Information regarding the patient’s prescriptions at other pharmacies (if any) should be obtained and documented when starting clozapine.

Note: some patients with mental health disorders may get certain medications (e.g., clozapine, depot injections) from hospital and/or clinic pharmacies in addition to their community pharmacy.

Psychiatrists ordering clozapine for patients should inform other prescribers of the addition of this medication, as it may impact medication choice for other medical conditions.

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As a result of the information that you provided, the psychiatrist is going to prescribe clozapine for Mr. Adams. As a pharmacist, you must monitor Mr. Adams’ lab tests, smoking status, medications, and weight/waist circumference.

Prior to dispensing the medication, you must ensure Mr. Adams is getting his blood taken for routine monitoring.

Mr. Adams currently smokes about 25 cigarettes per day. You should encourage and support him to quit smoking. Patients with mental health conditions bear the greatest burden of tobacco use. If he can quit or significantly reduce smoking during treatment, he may be able to decrease his dose of clozapine. His smoking status should be reviewed with each clozapine pickup.

Mr. Adams takes medications prescribed by a family physician who sees the residents at the group home. It is important for you to note all changes to medications to identify any potential impact to the clozapine treatment and/or lab tests.

Mr. Adams already has type 2 diabetes, and clozapine is associated with significant potential for weight gain and metabolic syndrome. It will be important to have a baseline weight and waist circumference noted in the pharmacy system and measure it weekly to biweekly for the first month or two of treatment. It is vital to identify any weight changes early, in order to minimize further risk.

A key component to providing care to individuals with mental health disorders, including those with TRS, is building rapport and trust. A therapeutic alliance is the degree to which individuals with mental illness and their healthcare providers are engaged in collaborative, purposive work.33 TRS is a chronic condition; so, pharmacists will have an opportunity to build therapeutic alliances over time. This can involve working with patients taking clozapine to identify treatment goals (e.g., adherence) and creating strategies to accomplish those goals. In addition, a therapeutic alliance will involve developing a bond between the pharmacist and the patient, built on trust, respect, and caring.33,34

Therapeutic alliances are thought to contribute to patients’ willingness to manage their own illnesses, thus improving health- and quality-of-life-related outcomes. Furthermore, there is evidence indicating that stronger therapeutic alliances are associated with increased medication adherence.35,36

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When building relationships with patients, pharmacists should:

What are the symptoms that trouble the person the most? How does the illness impact daily living, relationships, etc.?

What medications has the patient tried? What role does medication play in managing the illness? What adverse effects have been experienced? What has the patient heard about antipsychotics or clozapine specifically? What concerns are there? What does the patient hope the medication will do?

What has the individual’s past experience with pharmacies been like? Has the patient had positive interactions with the pharmacist and the pharmacy team? Have they experienced stigma?

Listen to the patient’s experiences without judgment.

Hold sensitive conversations in a private/quiet space; there is still stigma associated with mental illness and it is important to be sensitive to this when working with your patients.

1. Clozapine is the gold standard for treatment-resistant schizophrenia (TRS).

2. Clozapine is unique both clinically (i.e., decreased propensity to cause EPS) and pharmacologically (i.e., low affinity for D2 receptor).

3. Clozapine can take several weeks to months to have full effect; hence, patients may experience further improvements up to one year after being on a stable dose.

4. To maximize therapeutic benefit and minimize risks of adverse events, prescribers must consider numerous patient-related factors prior to initiating clozapine.

5. TRS is a chronic condition requiring long-term treatment with clozapine for most individuals. Pharmacists have a significant opportunity to maximize patient outcomes by building therapeutic relationships with their patients over time.

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1. Agid O, Foussias G, Sing S, et al. Can we prevent blood dyscrasia (leucopenia, thrombocytopenia) and epileptic seizures induced by clozapine. Where to position clozapine: re-examining the evidence. Can J Psychiatry. 2010;55:677-684.

2. Marder SR, Wirshing DA. Clozapine. In: Schatzberg A, Nemeroff C, eds. Textbook of Pyschopharmacology. 4th ed. Washington, DC: American Psychiatric Publishing, Inc.; 2009:555-571.

3. Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Pyschiatry. 2007;18:39-60.

4. Health Canada. Summary Safety Review – Clozapine – Assessing the effectiveness of monitoring for low numbers of white blood cells. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/clozapine-white-blood-cells.html. Updated July 26, 2018. Accessed February 7, 2021.

5. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789-796.

6. Remington G, Addington D, Honer W, et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry. 2017;62(9):604-616.

7. Howes OD, McCutcheon R, Agid O, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216-229.

8. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al. The schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010;36(1):94-103.

9. National Collaborating Centre for Mental Health Commissioned by the National Institute for Health and Clinical Excellence. Schizophrenia: Core interventions in the treatment and management of schizophrenia in primary and secondary care (update). Number 82. 2017.

10. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007;68(11):1751-1762.

11. Essali A, Al-Haj HN, Li C, et al. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009;(1):CD000059.

12. Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry. 2002;159(2):255-262.

13. Siskind D, McCartney L, Goldschlager R, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385-392.

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14. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600-610.

15. Kerwin R, Bolonna A. Management of clozapine-resistant schizophrenia. Adv Psychiatr Treatment. 2005;11:101-106.

16. Taylor DM, Smith L. Augmentation of clozapine with a second antipsychotic: a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand. 2009;119(6):419-425.

17. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005;162(1):130-136.

18. Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol. 2007;27(6):582-589.

19. Barbui C, Signoretti A, Mule S, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull. 2009;35(2):458-468.

20. Schulte P. What is an adequate trial of clozapine? Clin Pharmacokinet. 2003;42(7):607-618.

21. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006;354(5):472-482.

22. Chang JS, Ahn YM, Park HJ, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69(5):720-731.

23. Bilder RM, Goldman RS, Volavka J, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002; 159(6):1018-1028.

24. Purdon SE, LaBelle A, Boulay L. Neuropsychological change in schizophrenia after 6 weeks of clozapine. Schizophr Res. 2001;48(1):57-67.

25. Meltzer HY, Okayli G. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. Am J Psychiatry. 1995;152(2):183-190.

26. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91.

27. Conley RR. Optimizing treatment with clozapine. J Clin Psychiatry. 1998;59 Suppl 3:44-48.

28. Chong SA, Remington GJ, Bezchlibnyk-Butler KZ. Effect of clozapine on polypharmacy. Psychiatr Serv. 2000;51(2):250-252.

29. Glick ID, Zaninelli R, Hsu C, et al. Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior. J Clin Psychiatry. 2004;65(5):679-685.

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30. Citrome L, Volavka J, Czobor P, et al. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv. 2001;52(11):1510-1514.

31. Volavka J, Czobor P, Nolan K, et al. Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol. 2004;24(2):225-228.

32. Krakowski MI, Czobor P, Citrome L, et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2006;63(6):622-629.

33. Allen M, Le Cook B, Carson N, et al. Patient-provider therapeutic alliance contributes to patient activation in community mental health clinics. Adm Policy Ment Health. 2017; 44(4):431-440.

34. Murphy A, Phelan H, Haslam S, et al. Community pharmacists’ experiences in mental illness and addictions care: a qualitative study. Substance Abuse, Treatment, Prevention and Policy. 2016; 11:6-14.

35. Tessier A, Boyer L, Husky M, et al. Medication adherence in schizophrenia: The role of insight, therapeutic alliance and perceived trauma associated with psychiatric care. Psychiatric Res. 2017;257:315-321.

36. McCabe R, Bullenkamp J, Hansson L, et al. The therapeutic relationship and adherence to antipsychotic medication in schizophrenia. PLoS ONE. 2012;7(4):e36080.

In order to receive CE credits for this course, you must complete the CE test online at www.HealtheLearning.ca.