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Zubaida Rahman

on 13 April 2013

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Transcript of Clozapine

approved drug for: treatment-resistant schizophrenia
recurrent suicidal behavior in schizophrenia History of Clozapine Prototypical atypical anti-psychotic introduced in 1990 in the USA Tri-cyclic dibenzodiazepine derivative Neurological Mechanism
of Schizophrenia Neurological Mechanism
of Schizophrenia Serotonergic Pathway Dr. Zubaida Rahman Rph, PharmD, BCNP New York Presbyterian Hospital Clozapine Neurological Mechanism
of Schizophrenia Dopaminergic Pathway Clozapine has a high
affininty for the following
serotonergic receptors: 5HT1A
5HT7 Inverse Agonist

Inverse Agonist Partial Agonist Clozapine can block the constitutive activity
of these receptors, which is independent of 5HT
stimulation. Schizophrenia may involve disregulation
of 5HT and DA-mediated neurotransmission.
Clozapine restores a normal balance in
serotonergic and dopaminergic
neurotransmission in schizophrenic patients. Clozapine has a high affinity
for the following
dopaminergic receptors: D1
D5 Receptor blockage
in hippocampus. Receptor blockage in the amygdala,
medullar frontal cortex, and
mesocortical tract. Active receptor blockage
in mesolimbic tract, and weak
receptor blockage in basal ganglia. Clozapine binds to dopamine D4 receptor
more than any other anti-psychotic drug. I
ts affinity for mesolimbic and mesocortical tracts
is higher than its affinity for the
nigostriatal and tuberoinfundibular tracts. Mesolimbic Tract: Excess DA causes positive symptoms. Positive Symptoms: Hallucinations
Disorganized Speech
Behavioral Changes
Psychotic Agitation Negative Symptoms: Anhedonia
Affective flattening
Social Withdrawal Mesocortial Tract: DA deficit causes cognitive dysfunction
and negative symptoms. Nigrostriatal Tract: D2 receptor blockage results in EPS. Tuberoinfundibular Tract: D2 receptor activation
controls pituitary prolactin release Typical anti-psychotics primarily work only on the mesolimbic
and nigrostriatal tracts. Clozapine affects the mesolimbic and mesocortical tracts, and unlike typical anti-psychotic drugs, Clozapine has high 5HT2 to D2 receptor antagonism in the nigrostriatal and tuberoinfundibular tracts. Schizophrenia and
Neurotransmitters Clozapine is a strong antagonist at muscarinic cholinergic receptors: M1, M2, M3, M5 (drymouth, constipation, urinary retention, vision abnormalities) Clozapine is a adrenergic α1 and α2 blocker (hypotension, sedation, and tachycardia.) Clozapine produces massive increase in plasma NE levels (hypertension, improved cognition and anti-depressant effect). Clozapine antagonizes GABA receptors (seizures). Clozapine is a histamine receptor
antagonist: H1, H3, H4 (sedation, weight gain, increase in glucose and lipids.) Agranulocytosis Incidence: 1.3% of patients in clinical trials.
Life threatening adverse events cause the greatest
concerns. Hence, clozapine is reserved for only
treatment-resistant and recurrent suicidial patients
with Schizophrenia. Patients with myeloproliferative disorders, and severe granulocytopenia should not receive clozapine (CI.) Onset: in the first 3 months of drug therapy.
95% of the cases occur within the first 6 months. Risk Categories: Older patients, women,
cachectic individuals (CNR,) Ashkenazi Jewish individuals,
HLA-B38 phenotype individuals.
Asians are 2.4x more susceptible than Caucasians. In agranulocytosis, the ANC drops below 500 cells/mm³ of blood. Signs and symptoms: fever, sore throat, weakness, lethargy,
infections (pharyngitis,) rigors, and gingival bleeding. Possible Mechanisms:
1. Reactive intermediate metabolite
of Clozapine (nitrenium ion) causes oxidative stress
to peripheral neutrophils.

2. Direct cellular toxicity by formation of intracellular
super oxide anion, expression of pro-apoptotic genes with
glutathion depletion.

3. N-desmethylclozapine is the major active metabolite, and is toxic to hematopoietic precursors of both myeloid and erythroid lineage

4. Genetic factors, marked by major histocompatibility
complex haplotypes may be associated.

5. Role of human leukocyte antigen (HLA,) DR4, DQW3,
haplotypes in prediciting susceptibility in agranulocytosis

6. It has been theorized that eosinophillia (>500 cells/mm³)
predicts later agranulocytosis. Management Strategies:
Weekly monitoring of WBC and ANC count; avoid medications like carbamazepine, propylthiouracil, sulfonamides.
If patient develops agranulocytosis, D/C clozapine (medical emergency)
Broad spectrum antibiotics are started.
Filgrastim (rG-CSF) 300 mcg/day given SQ with the onset of agranulocytosis, increasing dose by 300 mcg/day for first 3 days to a total dose of 900 mcg/day until resolution.
Sargramostim (GM-CSF) 3 mcg/kg/day for 4 days.
Rechallenge is not encouraged. To reduce chances of rechallenge, a single national master file (non-rechallengable database) is maintained confidentially. Refrences Agranulocytosis Atkin, K., F. Kendall, D. Gould, H. Freeman, J. Liberman, and D. O'Sullivan. "Neutropenia and Agranulocytosis in Patients Receiving Clozapine in the UK and Ireland." The British Journal of Psychiatry 169.4 (1996): 483-88. Print. Ziegenbein, M., A. Steinbrechher, and A. Garlipp. "Clozapine-Induced Aplastic Anemia in a Patient With Parkinson’s Disease." Canadian Journal of Psychiatry 48.5 (2003): 352. Print. Robinson, Donald S. "Psychopharmacology Research Tutorial for Practitioners - Clozapine Agranulocytosis: Mechanism of Drug Toxicity." Primar Psychiatry 13.3 (2006): 27-29. Print. Gerson, Stanton L., Cheryl Arce, and Herbert Y. Meltzer. "N-desmethylclozapine: a Clozapine Metabolite That Suppresses Haemopoiesis." British Journal of Haematology 86.3 (1994): 555-61. Print. Meged, S., D. Stein, P. Sitrota, Y. Melamed, A. Elizur, I. Shmuelian, and E. Gazit. "Human Leukocyte Antigen Typing, Response to Neuroleptics, and Clozapine-induced Agranulocytosis in Jewish Israeli Schizophrenic Patients." International Clinical Psychopharmacology 14.5 (1999): 305-12. Print. Munro, J., D. O'Sullivan, C. Andrews, A. Arana, A. Mortimer, and R. Kerwin. "Active Monitoring of 12,760 Clozapine Recipients in the UK and Ireland. Beyond Pharmacovigilance." The British Journal of Psychiatry 175.6 (1999): 576-80. Print. Oren, R., E. Granat, S. Shtrussberg, and Y. Matzner. "Clozapine-induced Agranulocytosis Treated with Granulocyte Macrophage Colony Stimulating Factor." The British Journal of Psychiatry 162.5 (1993): 686-87. Print. Gullion, G., and H. S. Yeh. "Treatment of Clozapine-induced Agranulocytosis with Recombinant Granulocyte Colony-stimulating Factor." Journal of Clinical Psyschiatry 55 (1994): 401-05. Print. Lieberman, J. A., J. Yunis, and E. Egea. "HLA-B38, DR4, DQw3 and Clozapine-Induced Agranulocytosis in Jewish Patients With Schizophrenia." Archives of General Psychiatry 47 (1990): 945-48. Print. References Mechanism of Action Van Tol, Hubert H. M., James R. Bunzow, Hong-Chang Guan, Roger K. Sunahara, Philip Seeman, Hyman B. Niznik, and Olivier Civelli. "Cloning of the Gene for a Human Dopamine D4 Receptor with High Affinity for the Antipsychotic Clozapine." Nature 350.6319 (1991): 610-14. Print. Psychopharmacology (1989) Volume 99 suppl, Issue: S, publisher Springer Berlin/Heidelberg pages 518-527 Seizures References Seizures Devinsky, O., G. Honigfield, and J. Patin. "Clozapine‐related Seizures." Neurology 41.3 (1991): 369-437. Print. Freeman, David J., and L. Kola Oyewumi. "Will Routine Therapeutic Drug Monitoring Have a Place in Clozapine Therapy?" Clinical Pharmacokinetics 32.2 (1997): 93-100. Print. Wilson, W. H., and A. M. Claussen. "Seizures Associated with Clozapine Treatment in a State Hospital." Journal of Clinical Psyschiatry 55.5 (1994): 184-88. Print. Orthostatic Hypotension References Orthostatic Hypotension Donnelly, J., and A. Macleod. "Hypotension Associated with Clozapine after Cardiopulmonary Bypass." Journal of Cardiothoracic and Vascular Anesthesia 13.5 (1999): 597-99. Print. Schatz, Irwin J. Orthostatic Hypotension. Philadelphia: Davis, 1986. 1037-041. Print. Safferman, A. Z., J. M. Kane, J. S. Aronowits, M. F. Gordon, S. Pollack, and J. A. Lieberman. "The Use of Clozapine in Neurologic Disorders." Journal of Clinical Psyschiatry 55 (1994): 98-101. Print. Thulesius, O., and E. Berlin. "Dihydroergotamine Therapy in Orthostatic Hypotension Due to Psychotropic Drugs." Journal of Clinical Therapeutics and Toxicology 24 (1986): 465-67. Print. George, T. P., and L. C. Winther. "Hypertension after Initiation of Clozapine." American Journal of Psychiatry 153 (1996): 1368-369. Print. Ennis, L. M., and R. M. Parker. "Paradoxical Hypertension Associated with Clozapine." American Journal of Psychiatry 151.3 (1997): 462. Print. Rechlin, Thomas, Detlef Claus, and Maria Weis. "Heart Rate Variability in Schizophrenic Patients and Changes of Autonomic Heart Rate Parameters during Treatment with Clozapine." Biological Psychiatry 35.11 (1994): 888-92. Print. Li, June K.Y., Vincent T.F. Yeung, C. M. Leung, C. C. Chow, Gary T.C. Ko, W. Y. So, and C. S. Cockram. "Clozapine: a Mimicry of Phaeochromocytoma." Australian and New Zealand Journal of Psychiatry 31.6 (1997): 889-91. Print. A seizure is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain," resulting in physiological convulsions. Incidence: 5% of patients in clinical trials. Patients with severe CNS depression, comatose state or uncontrolled epilepsy should not receive clozapine (CI). Onset: 6 months to a year. Possible Mechanism:

1. Rapid dose titration

2. Dose related higher prevalence in patients treated with 600-900 mg per day.
1% in patients with dose < 300mg/day
3% in patients with dose = 300-600 mg/day
5% in patients with dose = 600-900 mg/day

3. Clozapine interferes with reuptake of catacholamines, and antagonizes GABA-A receptors. Signs and Symptoms:
Chewing movements
Difficulty talking
Eyes rolling up
Falling down
Inability to move
Lip smacking
Making sounds
Teeth clenching/grinding
Tongue biting
Twitching movements
Breathing difficulty
New onset stuttering, occupied by left side slowing. Management Strategies:
1. Gradual upward dose titration.
2. Lower dose if clozapine plasma threshold level is 350-420 ng/mL.
3. At baseline, and when daily dose exceeds 600 mg, routine EEG monitoring.
4. Caution in patients with history of seizures, or patients on epileptic drugs (Carbamazepine and Phenytoin.) Patients on benzodiazepine are more prone to respiratory depression and physical collapse while on clozapine.
5. While on clozapine, patients not to engage in any activity where sudden loss of consciousness can cause harm, like driving, swimming, climbing, or operating machinery.
6. If seizure occurs, clozapine is temporarily held or decreased by 50%, valproic acid inititated at 900 mg/day. Slowly reintroduce and retitrate clozapine once anti-convulsant dose is adequate. Myocarditis Myocarditis is the inflammation of the myocardium. Incidence: 5% in patients in clinical trials. 30 cases of myocarditis including 17 deaths have occured over last 10 years. Black box warning added to package insert in February 2002. Onset: Within first 21 days. (Median 15 days) Risk Categories: Family history of CVD, acute MI, HF, arrythmias, QTC prolonging drugs (amiodarone, azithromycin, and ziprasidone), drugs inhibiting metabolism of clozapine (ciprofloxacin, and carbamazepine.) Possible Mechanisms:
1. Type 1 Ig-E mediated acute hypersensitivity reaction.
2. Clozapine induced proinflammatory cytokine release and hypercatacholamine state. Signs and Symptoms:
Fever (heralding sign of clozapine induced myocarditis)
Chest pain
Hypereosinophilia Management Strategies:
1. Baseline ECG, Troponin I or T and C reactive protein levels at baseline, day 7, day 14, day 21 and day 28.
2. Baseline electrolytes, serum K+, and Mg++ levels.
3. Consultation with cardiologist in case of myocarditis. Withdrawal from clozapine should be under supervision of psychiatrist to avoid relapse of psychosis.
4. Treatment with Ace inhibitors (Lisinopril), β-blockers (Carvedilol) , diuretics (Furosemide), and Digoxin are used for immunomodulation as well as hemodynamic effect.
5. Selenium deficiency is associated with cardiomyopathy and myocarditis. Suggestion: beneficial to provide selenium supplementation to patients receiving clozapine. Hypersensitivity myocarditis by clozapine: massive myocardial infiltrates mainly represented by degranulated eosinophils are associated with fraying of the adjacent myocytes (arrows) [hematoxylin-eosin, original ×400]. Cardiomyopathy Cardiomyopathy is the chronic form of myocarditis. Onset: 2-36 months (Median 12 months.) 41 cases of cardiomyopathy including 10 deaths reported to FDA in the last 10 years. Signs and Symptoms:
Exertional dyspnea
Paroxysmal nocturnal dyspnea
Peripheral edema A drop in blood pressure (systolic = 25mmHg, diastolic = 10mmHg) when rising from sitting to standing. Incidence: 9% of patients in clinical trials. Most patients experienced syncope. Onset: Initial titration period with rapid upward dosing. Proposed Mechanisms:
1. Alpha-1 adrenergic blockage and resultant vasodilation.
2. Alpha-2 receptor antagonism.
3. Rapid dose escalation. Signs and Symptoms:
Rare cases of collapse with respiratory and cardiac arrest Risk Categories: Elderly patients. Management Strategies:
1. Slow upward dose titration.
2. Taking time when standing from a sitting or lying position in the morning or after meals.
3. Hypotension can be monitored by taking sitting and standing blood pressure regularly during therapy initiation or dose increase.
4. Ensure adequate fluid intake or salt for blood volume.
5. Support stockings.
6. Tilting the head of the bed slightly upward at night (increased RA pressure -> increased renin production -> increased blood volume.)
7. Tolerance develops in 4-6 weeks, if not:
Fludrocortisome 0.1- 1.0 mg/day
Dihydroergotamine 10mg/day Tachycardia Tachycardia is a heart rate that is greater than 100 bpm Incidence: 25% of patients in clinical trials. Onset: Inititation and titration phase. Possible Mechanisms:
1. Vagal inhibition by anticholinergic blockage of clozapine which leads to increased levels of plasma NE.
2. Rapidity of dose titration. (Transient Tachycardia)
3. Non reflex Tachycardia secondary to hypotension (peristant sustained tachycardia) Signs and Symptoms
Pulse increase of 10 bpm to 15 bpm.
Sustained tachycardia in all positions Management Strategies:
1. Lower dose or slower upward titration.
2. Tolerance usually develops after 4 to 6 weeks of treatment.
3. If persistent tachycardia with abnormal EKG, beta blockers like atenolol and propranolol can be used. Hypertension Incidence: 4% of patients in clinical trials. Onset: Initial titration period with rapid dose escalation. Possible Mechanisms:
1. Lab results of some patients showed elevated urinary levels of adrenaline and noradrenaline. Management Strategies:
1. Tolerance develops without clinical intervention.
2. Amlodipine, propranolol, or atenolol can be used Autonomic Nervous System
Side Effects Sialorrhea is profuse salivation during sleep or drooling during waking hours. Incidence: 31% of patients in clinical trials. Onset: During upward dose titration. Possible Mechanism:
1. Clozapine stimulates M4 muscarinic receptor in salivary glands.
2. Clozapine antagonizes α1 and α2 receptors in salivary glands -> blockage of receptors -> increased blood flow -> increased salivary flow.
3. Interference with normal swallowing reflex.
4. Clozapine dose dependent nocturnal hypersalivation with dosage 200-800 mg/day. Management Strategies:
1. Clozapine dose reduction if clinically feasible.
2. Sleeping with a towel over the pillow to absorb excess saliva.
3. Chewing sugar free gum to stimulate swallowing.
4. Anticholinergic drugs (last resort):
Amytryptyline 75-100 mg/day
Benztropine 1-2 mg/day
Ipratropium bromide (Atrovent) intranasal formulation (0.03%, 0.06%) 2 sprays SL up to 3 times daily
Atropine eye solution (1%) 1 drop SL at bedtime.
5. Aspiration precautions if severe hypersalivation Sweating Incidence: 4-6% of patients in clinical trials Onset: Within a month of initiation. Possible Mechanisms:
1. Circulating NE
2. Exocrine glands express M1 and M3 receptors. Clozapine full agonist at M4 receptor and partial agonist at M1, M2 and M3 receptors. Managment Strategies:
1. Tolerance develops after some time.
2. Biperiden (M1 receptor selective) titrated to 6 mg/day. Xerostomia (Dry Mouth) Incidence: 6% of patients in clincal trials Onset: During first few weeks of initiation. Possible Mechanism:
1. Blockage of muscarinic receptors by clozapine Managment Strategies:
1. Sipping water or sugarless drinks.
2. Avoid caffeine, tobbaco and alcohol.
3. Add humidifier to patient's room.
4. Chewing sugar free gum.
5. Using salivary substitutes (Oral Balance, Salivart) Visual Disturbances Incidence: 5% of patients in clinical trials. Mydriasis, eyelid disorder, and accomodation difficulties are reported. Onset: 6 months to 2 years Possible Mechanism:
1. Strong antagonist at cholinergic M1, M2, M3 and M5 receptors. Management Strategies:
1. Care should be taken in patients with narrow angle glaucoma. GI Side Effects Constipation Incidence: 14% in patients in clinical trials. Severe intestinal obstruction leading to fecal impaction, resulting in death. Patients with paralytic ileus should not receive clozapine (CI) Onset: During upward dose escalation. Proposed Mechanism:
1. Decreased peristalsis due to potent anticholinergic properties.
2. 5HT3 receptor antagonism in GI tract.
3. May affect 5HT3 and 5HT4 peripheral receptors, which causes impaired motility, leading to bowel obstruction.
4. When daily dose exceeds 150 mg/day. Management Stratgies:
1. Adequate hydration, high fiber diet and exercise.
2. Daily nursing flow sheet to document bowel habits.
3. Avoidance of excess calcium and anticholinergic medication.
4. Bulk laxatives (Lactulose, Psyllium.)
5. Stool softeners (Docusate.)
6. Cautiously lower dose of Clozapine
7. Stimulant laxatives for short period (Sennosides, Bisacodyl supp.)
8. Colonic Lavage (Golyetly) .
9. GI specialist for serious bowel obstruction.) Nausea Incidence: 5% of patients in clinical trials. Onset: Later in the course of treatment. Possible Mechanism:
1. When daily dose exceeds 150 mg.
2. Anticholinergic effect leading to delayed gastric emptying.
3. Increased salivation.
4. Direct effect on hypothalamus. Management Strategies:
1. Antacid and H2 blockers are used.
2. Caution using metoclopromide. Other GI Effects include elevated liver enzymes. Monitor LFT at baseline and periodically at initial phase of dose titration. Urinary Abnormalities Incontinence, Nocturnal Enuresis Incidence: Ranged from 0.23% to 30% of patients in clincal trials. This wide variation is due to underreporting, due to embarassment or social stigma. Onset: Initial titration period. Possible Mechanism:
1. α adrenergic antagonism, leading to decreased internal bladder sphincter tone.
2. Sedative properties of clozapine, leading to urinary retention, resulting in subsequent overflow. Management Strategies:
1. Avoid fluids in the evening, voiding before going to bed, scheduled night awakenings to empty the bladder can be practiced.
2. Enuresis alarm can be used.
3. Desmopressin (DDAVP) acetate administered intranasally 1 puff (10mcg) each nostril at QHS.
4. Oxybutynin (anticholinergic with antispasmodic properties can help enuresis plus urgency) 5-15 mg/day Endocrine and
Metabolic Disorders Weight Gain Incidence: 4-6% with therapeutic use of clozapine. Some studies report weight gain as high as 50% of patients. Onset: 3 months and onwards. Possible Mechanism:
1. 5HT2C antagonism.
2. H1 receptor linked activation of hypothalamic AMP-kinase, which is linked to increased food intake.
3. Increased insulin secretion, which affects glucose insulin homeostasis.
Induction of peripheral insulin resistance
Direct effect on beta cells (5HT1A)
4. Impaired growth hormone secretion
5. Appetite increase due to alleviation of negative symptoms.
6. Poor nutritional/sedentary lifestyle. Management Strategies:
1. Track weight and BMI at baseline, week 4, week 8, week 12, following initiation or change in therapy. Track quarterly thereafter.
2. Measure waist circumfrence (WHR) at baseline and anually thereafter.
3. Nutrtional and dietary counseling for patient.
4. Caloric restriction and excercise for thirty minutes daily. Hyperglycemia Many diabetes related consequences, which include: glucose intolerance, ketoacidosis, hyperosmolar coma, have been reported through case reports, retrospective chart reviews, and cross sectional studies. Possible mechanism:
1. Direct effect on beta cells of pancreas.
2. Dysregulates glucose metabolism by impairing the reaction of islet cells to glucose stimulation.
3. Direct muscarinic blockage on pancreatic islet cell. Management Strategies:
1. Monitor patient for signs or symptoms of polydipsia, polyurea, polyphagia and weakness.
2. Fasting blood glucose (FBG) at baseline, week 12 and anually thereafter.
3. Diet, exercise and nutritional education is recommended.
4. Patients with DM should be regularly monitored. Hyperlipidemia Onset: 10 weeks to 2 years. Compelling data indicates that clozapine increases triglyceride levels by 30%. Other authors suggest that an increase in TG levels is beneficial to psychiatric effect through stabilization of neuronal membranes. An increase also enhances fluidity of neuronal cell membranes, which leads to increased presynaptic reuptake of serotonin. Clozapine lipophilicity increases by interacting with VLDL fraction and helps its transport across BBB, which increases its pharmacological effect. . Management Strategies:
1. Fasting lipid profile at baseline, week 12 and then every 5 years. Sedation Incidence: Most common side effect, 39% of patients in clincal trials. Onset: early in the treatment process. Possible Mechanism:
1. Central antagonism of H1 receptors.
2. Adrenoreceptor blockade. Management Strategies:
1. Patient develops tolerance gradually usually within 4-6 weeks.
2. Most patients endure the side effects knowing that it will eventually diminish.
3. Give major portion of clozapine dose at bedtime.
4. Methylphenidate, dextroamphetamine have been used to counteract sedation (Caution: Using these medications can exacerbate psychosis.) Fever A fever of 100.4F (38C) is usually transient, benign and a self-limiting phenomenon with clozapine use. Incidence: 5% of patients in clinical trials. Onset: First 3-8 weeks of therapy. Possible Mechanism:
1. Flu like symptoms develop during titration period as a result of clozapine alpha-adrenergic properties.
2. Pyrexia may be one of the heralding signs of clozapine induced myocarditis. Management Strategies:
1. If fever is persistent, routine workup including: PE, WBC with differentials, urine analysis, chest X-Ray and blood culture, should be done to rule out: infection, agranulocytosis, and myocarditis. Neuroleptic Malignant Syndrome (NMS) Incidence: 1% of patients receiving clozapine with other neuroleptics. Onset: first 2 weeks of treatment. Signs and symptoms:
Fever over 102F
Elevated creatine phosphokinase (CPK > 1000 IU/L)
Increase in heart rate
Intense Diophoresis
Mental status change
AST and ALT elevation Management Strategies:
1. Rule out BZD withdrawal, systemic infection, serotonin syndrome and pneumonia.
2. Immediately discontinue clozapine. Intensive symptomatic treatment with IV fluids and cooling blankets.
3. Dantrolene, Bromocriptine have been used with medical monitoring. Rash Incidence: 2% of patients in clincal trials. Onset: During initiation and titration phase (9-15 days.) Possible Mechanism:
1. Drug hypersensitivity reaction. Signs and Symptoms:
Erythematous, papular pruritic rash
Rare case of bilateral pleural effusion Management Strategies:
1. D/C clozapine if hypersensitivity is suspected. Elderly Patients Clozapine is not approved for the treatment of patients with dementia related psychosis.
Elderly patients with dementia related psychosis treated with clozapine are at increased risk of death (Blackbox warning)
Elderly are more prone to clozapine side effects like sedation, orthostatic hypotension, anticholinergic side effects (constipation, urinary retention, dry mouth, tachycardia, blurred vision, confusion and delirium.)
Elderly are particularly susceptible to confusion, delirium (due to organic cognitive deficits) when treated with clozapine.
Clozapine is only effective in treatment of psychosis associated with Parkinson's Disease, or Lewy Body Dementia. Initial dose of clozapine is 6.25 - 12.5 mg/day.
Clozapine is not the first line agent for treatment of psychosis associated with Parkinson's Disease due to side effect profile in the elderly. Dosage Therapy interruption for 2 or more days = reinitiate at 12.5 mg once or twice a day.
Planned termination is a gradual dose reduction over a 1-2 week period. Abrupt discontinuation will result in recurrence of psychotic symptoms and rebound cholinergic symptoms.
Maximum dose for most patients is 900 mg/day.
Clinical plasma levels of clozapine is 350-420 ng/mL
Patients should be monitored for first three months after conversion from one formulation to another Metabolism Predominantly metabolized by hepatic isoenzyme CYP1A2.
CYP2D6 and CYP3A3 also contribute to clozapine metabolism.
Smoking tobacco, phenytoin, rifampin induce CYP1A2, which lowers clozapine levels.
Fluvoxamine inhibits CYP1A2, which increases clozapine levels.
Fluoxetine and paroxetine inhibit CYP2D6, which increases clozapine levels.
Fluconazole, pimozide, sparfloxacin should not be used with clozapine (CI.) Concluding Remarks Remarkable advantages of clozapine must be balanced against its ability to cause agranulocytosis, seizures, and myocarditis. Clinicians, by understanding the pathophysiological mechanism of the adverse effects of clozapine, can prevent its toxicity. Both the monetary and non-monetary costs add to its hestitancy of use amongst clinicians. Chemical name is 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine, C18H19ClN4. First introduced in Europe in 1971, voluntarily withdrawn in 1975 due to Agranulocytosis All patients are automatically entered into a national registry. Through this national registry, patients will recieve treatment under a registered physician with routine monitoring of WBC and ANC levels. Clozapine remains the gold standard to alleviate both negative and positive symptoms in treatment resistant and recurrent suicidal schizophrenic patients, with essentially no EPS or hyperprolactinemia. Kane et. al., published a landmark study in the Archives of General Psychiatry demonstrating how Clozapine is superior to Chlorpromazine in treatment resistant patients, where their respective efficacies were 30% and 4%.

Clozapine exhibited clear therapeutic superiority in all efficacy measures over risperidone in a double blind, comparative study of the management of severe chronic schizophrenic patients.

Inter SePT trial demostrated effectiveness of clozapine in reducing risk of recurrent suicidal behavior. Innovative design of an extremely important public health problem in a very high risk population. References Sialorrhea Hinkes, R., T. V. Quesada, and M. B. Currier. "Aspiration Pneumonia Possibly Secondary to Clozapine-Induced Sialorrhea." Journal of Clinical Psychopharmacology 16 (1996): 462-63. Print. Lapierre YD, Ghadirian A, St. Laurent J et al. Clozapine in acute schizophrenia—efficacy and toxicity. Curr Ther Res. 1980; 27:391-400. Product Information: clozaril(R), clozapine. Novartis, East Hanover, NJ, 2002. Antonello et al., psychiatry, neuroscience. 1999 24(3): 250. Sweating Richardson, C., D. L. Kelly, and R. R. Conley. "Biperiden for Excessive Sweating from Clozapine." American Journal of Psychiatry 158.8 (2001): 1329-330. Print. Drymouth Product information; Fazaclo(R) orally disintegrating tablets clozapine orally disintegrating tablets, Avanir pharmaceuticals, Aliso Viejo, CA 2007. Visual Disturbances Reynolds, Jeff (ed): Martindale: The Extra Pharmacopoeia (electronic version). Micromedex Inc, Denver, Colorado. 2000. Constipation Meltzer, H. "Effects on Serotonin and Dopamine Receptors in the Mechanism of Atypical Antipsychotic Drugs." European Neuropsychopharmacology 12 (2002): 164-65. Print. Gershon, Michael D., and Jan Tack. "The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders." Gastroenterology 132.1 (2007): 397-414. Print. Townsend, G., and D. Curtis. "Case Report: Rapidly Fatal Bowel Ischaemia on Clozapine Treatment." BMC Psychiatry 43rd ser. 6 (2006). Print. Nausea Burgeois, J. A., and K. G. Drexler. "Hypersalivation and Clozapine." Hospital and Community Psychiatry 42 (1991): 1174. Print. Lieberman, J. A., J. M. Kane, and C. A. Johns. "Clozapine: Guidelines for Clinical Management." Journal of Clinical Psyschiatry 50 (1989): 329-38. Print. Liver Hummer, M. "Hepatotoxicity of Clozapine." Schizophrenia Research 18.2-3 (1996): 126-27. Print. Sedation Cohen, S. (1992). Sedation. In: Yesavage, J., ed. Clozapine: A Compendium of Selected Readings. Stanford, CA: Sandoz Pharmaceuticals Corporation, 1992 References Urinary Abnormalities Fuller, Matthew A., Mary C. Borovicka, George E. Jaskiw, Michelle R. Simon, Kong Kwon, and P. Eric Konicki. "Clozapine-Induced Urinary Incontinence: Incidence and Treatment With Ephedrine." The Journal of Clinical Psychiatry 57.11 (1996): 514-18. Print. Lieberman, J. A. "Maximizing Clozapine Therapy: Managing Side Effects." Journal of Clinical Psyschiatry 59 (1998): 38-43. Print. Beach, P. S., R. E. Beach, and L. R. Smith. "Hyponatremic Seizures in a Child Treated With Desmopressin to Control Enuresis: A Rational Approach to Fluid Intake." Clinical Pediatrics 31.9 (1992): 566-69. Print. Frankenburg, F. R., J. C. Kando, F. Centorrino, and J. M. Gilbert. "Bladder Dysfunction Associated with Clozapine Therapy." Journal of Clinical Psyschiatry 59 (1996): 39-40. Print. Steingard, S. "Use of Desmopressin to Treat Clozapine-induced Nocturnal Enuresis." Journal of Clinical Psyschiatry 51 (1994): 315-16. Print. Kronig, M. N., R. A. Munne, S. Szymanksi, and A. Z. Safforman. "Plasma Clozapine Levels and Clinical Response for Treatment-refractory Schizophrenic Patients." American Journal of Psychiatry 152 (1995): 179-82. Print. Weight Gain Briffa, Dianne, and Thomas Meehan. "Weight Changes during Clozapine Treatment." Australian and New Zealand Journal of Psychiatry 32.5 (1998): 718-21. Print. Cohen, S., J. Chiles, and A. MacNaughton. "Weight Gain Associated with Clozapine." American Journal of Psychiatry 147 (1990): 503-04. Print. Hasnain, Mehrul, W. Victor R. Vieweg, Sonja K. Fredrickson, Mary Beatty-Brooks, Antony Fernandez, and Anand K. Pandurangi. "Clinical Monitoring and Management of the Metabolic Syndrome in Patients Receiving Atypical Antipsychotic Medications." Primary Care Diabetes 3.1 (2009): 5-15. Print. Thieson, F. M., S. Cichon, and A. Linden. "Clozapine and Weight Gain." American Journal of Psychiatry 158.5 (2001): 816. Print. Myocarditis Gragas, M., C. F. Washburn, and C. F. Caley. "Clozapine-induced Myocarditis: 2 Case Reports." Journal of Clinical Psychopharmacology 30.1 (2010): 91-92. Print. Leo RJ, Kreeger JL, Kim KY. Cardiomyopathy associated with clozapine. Ann. Pharmacother 1996; 30: 603–605. 7 Vaddadi, K. S., E. Soosai, and G. Vaddadi. "Low Blood Selenium Concentrations in Schizophrenic Patients on Clozapine." British Journal of Clinical Pharmacology 55.3 (2003): 307-09. Print. Conclusion Buchanan, RW., Brier, A., Kirkpatrick, B., Ball, P., Carpenter, W.T., (1998) Positive and negative symptoms response to clozapine in schizophrenic patients without the deficit syndrome. American Journal of Psychiatry. I-123 IQNB SPECT
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