Clozapine Study Guide
Description
Clozapine is an FDA-approved second-generation antipsychotic medication used to treat psychotic symptoms in the mentally ill, especially schizophrenic patients, as a second-line medication (U.S. Food & Drug Administration). Clozapine is used to manage recurrent suicidal behavior in schizophrenia and schizoaffective disorders.
It is marketed as Clozaril, Fazaclo ODT, Versacloz, CloZAPine Synthon, Denzapine, and Zaponex. The REMSprogram regulates these manufacturers to provide a central prescribing and monitoring center (Haidary & Pathy, 2021). Clozapine is an effective medication used for refractory bipolar disorder as an off-label medication.
Classification
Clozapine is a second-generation antipsychotic- an atypical antipsychotic in the class.
Mechanism of Action
Clozapine binds to the serotonin and dopamine receptors. It has a high affinity for D4 receptors but also binds to D1, D2, D3, and D5 receptors (Haidary & Padhy, 2021). The drug is more active in the limbic than striatal regions; hence, less extrapyramidal effects are experienced in other medications. The drug is a partial serotonin receptor agonist, thus its ability to improve anxiety, depression, and negative symptoms. The drug also acts on adrenergic, cholinergic, and histamine receptors hence its side effects.
Side effects
The mnemonic CLOZIE can be used to indicate its side effects
C- cytopenia (agranulocytosis) (Mijovic & MacCabe, 2020)
L- bradycardia and reflex tachycardia
O- obesity- weight gain, constipation,
Z- Zap-sedation, drowsiness, dizziness, constipation, and excessive salivation
I- Incontinence- urinary incontinence
E- epilepsy in non-epileptic patients due to the lowered threshold and worsening seizures in epileptic patients (U.S. Food & Drug Administration)
Comorbidities associated with clozapine
The most severe side effect of the drug is neutropenia leading to severe bone infections, hence the need to monitor absolute neutrophil count for patients on clozapine. Haidary and Padhy (2021) note that clozapine is also associated with increased risk and incidences of myocarditis. In addition, other comorbidities include neutropenia, hypotension, bradycardia, and syncope. In addition, patients can experience seizures, myocarditis, and an increased risk of death.
Pharmacokinetics
Clozapine is well-absorbed, with 6-70% bioavailability after oral consumption due to first-pass metabolism (U.S. Food & Drug Administration). The major metabolite, norclozapine, is metabolically active, but the other metabolites are for excretion in urine and feces. The cytochrome P450 isoenzyme 1A2 is the major enzyme in clozapine metabolism.
Thus, agents that induce or inhibit the enzyme can affect its metabolisms and subsequent bioavailability. For example, cigarette smoke indices the CYP450 system, and thus the non-smokers require almost a double dose to achieve the same drug plasma level as non-smokers (U.S. Food & Drug Administration). The peak plasma concentration time is 21/2 hours, and food does not affect its absorption. Thus, it can be taken with food, before or after food.
Half-life
Figure 3 Clozapine half-life
Half-life is the amount of time taken for the plasma volume of a drug to reduce by half. The half-life of clozapine is 14 hours, but that depends on the dose and frequency. Thus, studying the plasma levels can help predict drug compliance, metabolic status, possible interference, dose-effect relationship, and toxicity monitoring.
Appropriate dosing, administration route, and any considerations for dosing alterations
The ideal dosage for clozapine is 12.5mg orally once daily. The dose is then titrated to 20 -50mg daily, given in divided doses. Subsequent increments after two weeks can entail 100mg weekly, and the maximum dose is 900mg per day, above which toxicity sets in (Medicine.com, n.d.).
Clozapine treatment is commenced at a low dose due to the severe drug side effects. The doses also vary, with younger patients requiring smaller doses and older adults much lower doses. Maintenance therapy is usually best done at night before bedtime to promote quality sleep because the drug induces drowsiness, affecting work quality.
Dosage alteration to reduce the dose is necessary for renal and liver disorders because the drug is metabolized in the liver and excreted in bile and urine. The drug should be withdrawn in cases of neutropenia. Reduce dose when using a concurrently CYP450 1A2 inhibitor, such as an increased dose when using a CYP450 1A2 inducer such as carbamazepine. Routine dose-effect monitoring for weak inducers and inhibitors of the CYP450 1A2 is recommended.
Lab monitoring
WBC count and WBC differentials
Urea ad electrolytes due to risk for QT elongation (Funk et al., 2018)
EKG/ECG to monitor cardiac function
Weight, lipid profile, and blood sugar measurements (HbA1c)
Suicidal tendencies and behaviors assessment
Contraindications
Clozapine is contraindicated in patients with uncontrolled epilepsy, myeloproliferative disease, and agranulocytosis secondary to prior clozapine treatment (Funk et al., 2018).
It is contraindicated in pregnant and breastfeeding mothers.
De Leon et al. (2020) notes that the clozapine medication dose is altered for patients on fluvoxamine and requires magnitude dose adjustment if the two drugs are used concurrently because it inhibits clozapine metabolism.
Combining the drug with aripiprazole may worsen cardiovascular symptoms
Alcohol increases the central nervous system suppression hence worsening drowsiness, dizziness, and poor attention
Legal and Ethical Considerations
Clonazepam is used in patients who have been resistant to other medications. It is important to consider the potential for morbidities in immunocompromised patients, issues such as drug adherence, and the importance of a treatment assistant. These patients should have a treatment companion who monitors their medication adherence and other symptoms.
Convincing schizophrenic patients to involve their family members in their management is challenging but vital (Stern et al., 2016). Most importantly, care providers should weigh the drug’s benefits against the risks for individual patients before initiating therapy.
Patient Education Pertinent to the drug
Patient education often entails patient and family education. It should entail information on side effects and risk for agranulocytosis and participation in the REMS program for monitoring (De Leon et al., 2020). Information on risk for bradycardia, syncope, and effects on thinking, judgment, and motor skills.
After missing the drugs for two days, the patient should also visit the healthcare provider. In addition, contact the healthcare professional if pregnant, breastfeeding, or planning to be pregnant.
References
De Leon, J., Ruan, C. J., Schoretsanitis, G., & De las Cuevas, C. (2020). A rational use of clozapine based on adverse drug reactions, pharmacokinetics, and clinical pharmacopsychology. Psychotherapy and Psychosomatics, 89(4), 200-214. https://doi.org/10.1159/000507638
Funk, M. C., Beach, S. R., Bostwick, J. R., Celano, C. M., Hasnain, M., Pandurangi, A., Khandai, A., Taylor, A., Levenson, J. L., Riba, M., & Kovacs, R. J. (2018). Resource document on QTc prolongation and psychotropic medications. American Psychiatric Association. https://www.psychiatry.org/File%20Library/Psychiatrists/Directories/Library-and-Archive/resource_documents/Resource-Document-2018-QTc-Prolongation-and-Psychotropic-Med.pdf
Haidary, H. A., & Padhy, R. K. (2021). Clozapine. In StatPearls [Internet]. StatPearls Publishing.
Medicine.com (n.d.). Clozapine. https://www.medicine.com/drug/clozapine/hcp
Mijovic, A., & MacCabe, J. H. (2020). Clozapine-induced agranulocytosis. Annals of hematology, 99(11), 2477-2482. https://doi.org/10.1007/s00277-020-04215-y
Stern, T. A., Favo, M., Wilens, T. E., & Rosenbaum, J. F. (2016). Massachusetts General Hospital psychopharmacology and neurotherapeutics. Elsevier.
U.S. Food & Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
Study Guide for Medication Treatment Schizophrenia Spectrum and Other Psychosis Disorders
Please be mindful of plagiarism and APA format, I have included the rubric. Please use my course resources as one of my references as instructed. Please include Stern, T. A., Favo, M., Wilens, T. E., & Rosenbaum, J. F. (2016). Massachusetts General Hospital psychopharmacology and neurotherapeutics. Elsevier.
Learning Resources
Required Readings (click to expand/reduce)
Freudenreich, O., Goff, D. C., & Henderson, D. C. (2016). Antipsychotic drugs. In T. A. Stern, M. Favo, T. E. Wilens, & J. F. Rosenbaum. (Eds.), Massachusetts General Hospital psychopharmacology and neurotherapeutics (pp. 72–85). Elsevier.
American Psychiatric Association. (2019). Practice guideline for the treatment of patients with schizophrenia. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/Clinical%20Practice%20Guidelines/APA-Draft-Schizophrenia-Treatment-Guideline.pdf
Clozapine REMS. (2015). Clozapine REMS: The single shared system for clozapine. https://www.clozapinerems.com/CpmgClozapineUI/rems/pdf/resources/Clozapine_REMS_A_Guide_for_Healthcare_Providers.pdf
Funk, M. C., Beach, S. R., Bostwick, J. R., Celano, C. M., Hasnain, M., Pandurangi, A., Khandai, A., Taylor, A., Levenson, J. L., Riba, M., & Kovacs, R. J. (2018). Resource document on QTc prolongation and psychotropic medications. American Psychiatric Association. https://www.psychiatry.org/File%20Library/Psychiatrists/Directories/Library-and-Archive/resource_documents/Resource-Document-2018-QTc-Prolongation-and-Psychotropic-Med.pdf
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2), 261–276. https://doi.org/10.1093/schbul/13.2.261
Levenson, J. C., Kay, D. B., & Buysse, D. J. (2015). The pathophysiology of insomnia. Chest, 147(4), 1179–1192. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388122/
McClellan, J. & Stock. S. (2013). Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. Journal of the American Academy of Child and Adolescent Psychiatry, 52(9), 976–990. https://www.jaacap.org/article/S0890-8567(09)62600-9/pdf
Naber, D., & Lambert, M. (2009). The CATIE and CUtLASS studies in schizophrenia: Results and implications for clinicians. CNS Drugs, 23(8), 649–659. https://doi.org/10.2165/00023210-200923080-00002
Utah State University. (n.d.). Creating study guides. https://www.usu.edu/academic-support/test/creating_study_guides
Medication Resources (click to expand/reduce)
U.S. Food & Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
Note: To access the following medications, use the Drugs@FDA resource. Type the name of each medication in the keyword search bar. Select the hyperlink related to the medication name you searched. Review the supplements provided and select the package label resource file associated with the medication you searched. If a label is not available, you may need to conduct a general search outside of this resource provided. Be sure to review the label information for each medication as this information will be helpful for your review in preparation for your Assignments.
amisulpride
aripiprazole
asenapine
brexpiprazole
cariprazine
chlorpromazine
clozapine
flupenthixol
fluphenazine
haloperidol
iloperidone
loxapine
lumateperone
lurasidone
olanzapine
paliperidone
perphenazine
pimavanserin
quetiapine
risperidone
sulpiride
thioridazine
thiothixene
trifluoperazine
ziprasidone
Optional Resources (click to expand/reduce)
Chakos, M., Patel, J. K., Rosenheck, R., Glick, I. D., Hammer, M. B., Tapp, A., Miller, A. L., & Miller, D. D. (2011). Concomitant psychotropic medication use during treatment of schizophrenia patients: Longitudinal results from the CATIE study. Clinical Schizophrenia & Related Psychoses, 5(3), 124–134. https://doi.org/10.3371/CSRP.5.3.2
Fangfang, S., Stock, E. M., Copeland, L. A., Zeber, J. E., Ahmedani, B. K., & Morissette, S. B. (2014). Polypharmacy with antipsychotic drugs in patients with schizophrenia: Trends in multiple health care systems. American Journal of Health-System Pharmacy, 71(9), 728–738. https://doi.org/10.2146/ajhp130471
Lin, L. A., Rosenheck, R., Sugar, C., & Zbrozek, A. (2015). Comparing antipsychotic treatments for schizophrenia: A health state approach. The Psychiatric Quarterly, 86(1), 107–121. https://doi.org/10.1007/s11126-014-9326-2
Assignment: Study Guide for Medication Treatment Schizophrenia Spectrum and Other Psychosis Disorders
Psychosis and schizophrenia greatly impact the brain’s normal processes, which interfere with the ability to think clearly. When symptoms of these disorders are uncontrolled, patients may struggle to function in daily life. However, patients often thrive when properly diagnosed and treated under the close supervision of a psychiatric mental health practitioner. For this Assignment, you will develop a study guide for an assigned psychotropic agent for treating patients with Schizophrenia Spectrum and Other Psychotic Disorders. You will share your study guide with your colleagues. In sum, these study guides will be a powerful tool in preparing for your course and PMHNP certification exam.
To prepare for this Assignment:
Review this week’s Learning Resources, including the Medication Resources indicated for this week.
Reflect on the psychopharmacologic treatments you might recommend for treatment of patients with Schizophrenia Spectrum and Other Psychotic Disorders.
Research your assigned psychotropic medication agent using the Walden Library. Then, develop an organizational scheme for the important information about the medication.
Review Learning Resource: Utah State University. (n.d.). Creating study guides. https://www.usu.edu/academic-support/test/creating_study_guides
The Assignment
Create a study guide for your assigned psychotropic medication agents. Your study guide should be in the form of an outline with references, and you should incorporate visual elements such as concept maps, charts, diagrams, images, color coding, mnemonics, and/or flashcards. Be creative! It should not be in the format of an APA paper. Your guide should be informed by the FDA-approved and Evidenced-Based, Clinical Practice Guidelines Research but also supported by at least three other scholarly resources.
Areas of importance you should address, but are not limited to, are:
Title page
Description of the Psychopharmacological medication agent including brand and generic names and appropriate FDA indication uses
Any supporting, valid and reliable research for non-FDA uses
Drug classification
The medication mechanism of action
The medication pharmacokinetics
The medication pharmacodynamics
Mechanism of Action
Appropriate dosing, administration route, and any considerations for dosing alterations
Considerations of use and dosing in specific specialty populations to consider children, adolescents, elderly, pregnancy, suicidal behaviors, etc.
Definition of Half-life, why half-life is important, and the half-life for your assigned medication
Side effects/adverse reaction potentials
Contraindications for use including significant drug to drug interactions
Overdose Considerations
Diagnostics and labs monitoring
Comorbidities considerations
Legal and ethical considerations
Pertinent patient education considerations
Reference Page
Note: Support your rationale with a minimum of five academic resources. While you may use the course text to support your rationale, it will not count toward the resource requirement. You should be utilizing the primary and secondary literature.
Reminder : The College of Nursing requires that all papers submitted include a title page, introduction, summary, and references. The Sample Paper provided at the Walden Writing Center provides an example of those required elements (available at https://academicguides.waldenu.edu/writingcenter/templates/general#s-lg-box-20293632). All papers submitted must use this formatting.