Clozapine and Schizophrenia

In Canada, it’s estimated that 1 in 100 people are living with schizophrenia. While at first it might seem like a low number, the burden of the disease is far-reaching thus affecting more than the person who is diagnosed. 

Cardinal symptoms of schizophrenia include the presence of hallucinations, delusions, social withdrawal, reduction of executive functioning, disorganized speech and the presence of mood symptoms.  

Schizophrenia will impact a person’s ability to function in society impacting their ability to think clearly, make decisions and communicate with others. 

The effects of living with schizophrenia are widespread and people living with the disease have a shortened life expectancy of 20 years. This is typically due to high rates of substance dependence/ abuse, comorbid physical conditions such as cardiovascular disease, obesity and higher rates of suicide.  

The essential role of nurses in providing care to people living with schizophrenia is all encompassing. As nurses are on the floor interacting with the patient, they are the health care providers that establish trust and rapport. This relationship helps to reduce self-stigma of the disease the patient may be feeling and encourages adherence to drug therapy and management of the disease. 

Schizophrenia is a lifelong disease and building this therapeutic relationship with your patient is essential for ongoing recovery and to take control of one’s life.  

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What is Schizophrenia?

Schizophrenia is a mental illness that will affect a person’s perception of reality and how they relate to others. This disorder impacts both males and females almost equally but is more prevalent in the lower socioeconomic class. The social drift theory suggests that the impacts of schizophrenia on a person’s functioning result in disengagement from society and a dissent of their status in society. 

In males, the first episode of psychosis usually occurs in the late teens to early twenties. In females, the first episode will usually occur in the later twenties. The onset is accompanied by a warning prodromal period of a decline of function with characteristics of social withdrawal, mood swings, irritability and poor hygiene. 

When the disease is active, symptoms are classified into four different categories.

Positive Symptoms:

• Delusions (distorted thinking or beliefs)
• Hallucinations (distorted perceptions such as hearing  voices that aren’t there)
• Aggressions and hostility
• Disorganized speech

Negative Symptoms:

• Social withdrawal
• Difficulty expressing emotions
• Loss of pleasure and motivation

Cognitive Symptoms:

• Difficulty concentrating
• Attention deficits 
• Memory impairment

Mood Symptoms:

• Depression
• Anxiety
• Suicidal thoughts

The diagnosis of schizophrenia is primarily a clinical one. A physician or psychologist will assess if a person’s symptoms align with a schizophrenia as detailed in the Diagnostic Statistical Manual of Mental Disorders (DSM-5).

Management: 

Symptoms of schizophrenia are thought to be caused due to dysregulation in the dopamine pathways. Serotonin pathways often work synergistically with dopamine pathways, which is why the primary medications used to manage schizophrenia target dopamine and serotonin receptors.

The mainstay medications for schizophrenia are antipsychotics. There are 3 different medication classes for antipsychotics and each of these medication classes have significant risks and benefits (as outlined below). 

In addition, antidepressants, mood stabilizers and sedatives may be used to manage comorbid mental health conditions or side effects from the antipsychotics. 

Prompt initiation of therapy and management of symptoms is associated with better outcomes. The selection of an antipsychotic will be based on clinician judgement, patient’s symptoms (i.e targeting more positive symptoms than negative.) and weighing the risks vs benefits of a medication for a patient. 

When first line options have failed to control a patient’s symptoms, clozapine, a second generation antipsychotic, will be considered.     

Below is a summary of medications commonly used in management of symptoms of schizophrenia.

While various medications and treatments can be explored, the rest of this article will focus on clozapine, and look at why and how we monitor clozapine and the essential role you have as nurses.

Clozapine

Clozapine is a second generation antipsychotic that was first introduced to the Canadian market in the 1960’s. However, in 1975, it was withdrawn from the market due to reports of patient developing agranulocytosis (low white blood cell count) and subsequent development of fatal infections. In 1991, it was reintroduced into the market but had new strict monitoring protocols. 

The use of clozapine continues to be limited due to side effects such as sedation, hypotension, tachycardia and hypersalivation. More serious side effects include agranulocytosis, seizures  and myocarditis.  

Despite its risks, clozapine remains an essential drug in the management of schizophrenia as it can work when multiple treatment regimes have failed and has a significant role in suicidality. In clinical trials it has been shown effective in managing positive and negative symptoms. It continues to be used today in patients with treatment resistant schizophrenia.

Monitoring of Clozapine

1. Baseline complete blood cell count (CBC) with differential prior to initiation of medication

Prior to initiating treatment, it’s important to ensure that the baseline absolute neutrophil count is within a normal level. In addition to ensuring safe initiation, baseline tests help establish where a patient is at prior to starting a drug and will help establish how a drug may be affecting them.

2. Enrollment and approval into the manufacturer’s network 

Clozapine is supplied under the brand name Clozaril and various other generic suppliers are available. Each supplier has specific monitoring protocols and needs to be able to access the patient’s blood work to ensure patient safety. 

There are 3 main monitoring networks available in Canada, namely

• CSAN© is the network for Clozaril (Novartis)
• GenCan© is the network for Mylan-clozapine
• AAspire© is the network for AA-clozapine 

Prior to administering the drug, the network must approve the patient’s enrollment. The brands are not interchangeable.

3. Ongoing monitoring

Although the risk of agranulocytosis is the greatest in the first 6 months of initiation, the risk remains throughout treatment. After initiating the medication, ongoing blood work is required.

• First 6 months: Weekly CBC with differential 
• Next 6-12 months: CBC with differential every 2 weeks
• After 12 months, CBC with differential every 4 weeks

If the absolute neutrophil count falls below the threshold, CBC monitoring may increase and clozapine may be assessed for discontinuation. These lab values will be monitored by the manufacturer, the pharmacists and the physician. 

4. If discontinued, continued follow-up for 4 weeks

*Blood concentration levels are not routinely monitored as therapeutic (effective/safe) levels are not well established and are patient specific. As medication adherence is a concern due to the nature of the disease, blood concentration clozapine levels can be useful in determining compliance.  

Education Points

1. Importance of compliance 

In order for clozapine to be effective, proper adherence to the prescribed regimen is essential. If a patient is not adherent to their medication regime, they are at risk of relapsing which may lead to hospitalization. However, compliance in patients living with schizophrenia remains a major issue due to reasons such as lack of medication insight, denial of the medical condition or depression/suicidality. 

If a patient is noncompliant with clozapine, it’s important for this to be detected as after two days of missed doses, clozapine must be reintroduced at a lower dose. Compliance has implications on the dose and safety of the drug.  

2. Interactions

As clozapine is extensively metabolised by CYP450 enzymes, it has a lot of drug interactions. These interactions will be flagged and adjusted by pharmacy. However, a major interaction that every nurse should be aware of is smoking when on clozapine.

The schizophrenic population has a higher smoking rate than the general population so this interaction is relevant to a large number of patients. In addition, given that clozapine is reserved in situations where schizophrenia is resistant and a patient has relapsed, often it’s initiated in hospital. 

Hospitals have varying policies regarding smoking and while admitted to hospital, a patient may transiently not be able to smoke and will instead be provided with nicotine replacement therapy (NRT) to manage cravings. An individual’s smoking habit may also just normally fluctuate.   

When an individual stops smoking while taking clozapine, blood levels can rise to toxic levels. It is not the nicotine in cigarettes that breaks down clozapine but the tar and hydrocarbons in cigarettes. 

Even if a patient uses NRT, it will not affect the levels the way cigarettes do. On discharge, a patient may resume their regular smoking habit which may lead to sub therapeutic clozapine levels leading to treatment failure.  

Gaining a baseline understanding of a patient’s regular smoking habit, building an open relationship with a patient using clozapine and frequent monitoring is essential to manage this interaction.

3. Side effects to watch for

In addition to monitoring their white blood cell count, patients should be monitored for signs of infections such as fever, malaise, flu-like symptoms or weakness. If this is detected, an emergency CBC may be ordered and the physician in charge should be notified.   

Myocarditis and cardiomyopathy are also serious side effects that can be caused from use of clozapine. Patients should also be monitored for signs and symptoms of heart failure such as chest pain, difficulty breathing or a dry cough. If these occur, the patient should be referred to the physician and clozapine will be assessed for discontinuation.

Quality of life can also be impacted by the other side effects of clozapine such as constipation and hypersalivation. Optimizing laxative use and monitoring their bowel routine is vital in ensuring there are no complications from constipation. Hypersalivation can be managed through providing a patient with a “clozapine pillow”or pharmacologically with sublingual atropine.

The Essential Role of Nurses in the Collaborative Team

Adherence

In a mental health hospital, nurses are responsible for the administration of medications. Recovery from a relapse is directly tied with adhering to a prescribed regimen. However, in schizophrenia, there is a challenge with adherence even with nurses administering the medication. 

When administering clozapine, nurses must verify that a patient is actually taking the dose and not cheeking it! If a nurse is suspicious or unsure, this should be flagged to the prescriber for their own investigation. This is important in detecting if treatment failure is occuring or if non-adherence is the issue. Missed doses need to be properly documented and flagged to the prescriber as this will affect the strength of the medication that can be safely administered.

Monitoring

As nurses are on the floor and directly interacting patients, often they will be the first to detect side effects to medications. With clozapine, as the greatest risk of side effects are upon initiation of the medication, nurses have a vital role in observing signs and symptoms that may warrant the discontinuation of clozapine. 

With mental health medications, often the difference isn’t noticed first by patients but the people close to them. Nurses also have a role in providing insight into the efficacy of a treatment plan for a patient.    

Building a relationship with the patient and patient education

In a psychiatric setting, nurses have the opportunity of building relationships with their patients who often feel really alone in their mental illness. In schizophrenia, a lot of patients experience shame and denial and it’s up to health care professionals to remove the stigma so that patients will be comfortable accessing care. 

Nurses are often the healthcare professional that these patients will interact the most with; so building trust is key. 

Maintaining a message of hope will encourage adherence, patient education (i.e. why we monitor, when to talk to your physician, how to manage side effects) will allow for the safe use of antipsychotics and building an open relationship with patients will help with the detection of toxicity or manage interactions such as smoking. 

Conclusion

Schizophrenia is a psychiatric disease characterized by hallucinations and delusions. In refractory cases where multiple treatment options have failed, clozapine will be initiated with specific monitoring protocol. While clozapine is an exceptional drug that can restore quality of life for patients, it also bears the risk of causing fatal neutropenia and agranulocytosis.  

As nurses, you are the primary health care professional that administers clozapine, observes signs and symptoms of toxicity and detects changes in patients behavior. An understanding of how and why we monitor clozapine is important to ensure safe administration of the drug. Additionally, providing insight to the prescriber on adherence and flagging manifestations of toxicity are also key roles of nurses in the use of clozapine. 

Resources:

For more information, there are references available on each of the companies monitoring networks:CSAN©, GenCan©  or AAspire©

Author Bio  

Azra Chatur, BScPharm

Azra is a pharmacy graduate from the University of Alberta. All aspects of pharmacy and healthcare interest her but the majority of her experience has been focussed on long term care, geriatrics and community pharmacy. Writing is her passion and she is excited to be able to share her pharmaceutical knowledge with nurses! If you have questions don’t hesitate to connect with her on Linkedin.