Antipsychotics: The Essentials Module 4 Metabolic & Other Adverse Effects Flavio Guzmán, MD

Outline Metabolic effects Hyperprolactinemia Cardiovascular effects Anticholinergic effects Sedation Agranulocytosis Other effects

Metabolic Side Effects Weight Gain Diabetes Dyslipidemia

Weight Gain Why is it important? Schizophrenia patients are more likely to be overweight or obese than individuals without schizophrenia. Affects self-image. Cause of poor treatment adherence. Serious effects on health and life expectancy (hypertension, CAD, T2DM, stroke). Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Weight Gain: Possible Mechanisms Changes in appetite and satiety mediated by H1 antagonism. Antagonism of 5HT2C receptors might also contribute.

Weight Gain: Three Levels of Risk Level of risk Antipsychotic High Clozapine Olanzapine Intermediate Risperidone Quetiapine Little or no significant weight gain Aripiprazole Ziprasidone Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-72.

Weight Gain: Monitoring Frequent monitoring of BMI (kg/m2) BMI 25-30: Overweight BMI ˃ 30 : Obese Waist circumference monitoring Central obesity is a risk factor for diabetes, hypertension and dyslipidemia Abdominal obesity: Men: ˃ 102 cm (˃ 40 in.) Women: ˃ 88 cm (˃ 35 in.) Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-72.

Diabetes The prevalence of T2DM is twice as high among patients with schizophrenia as in the general population. Clozapine and olanzapine are more often associated with T2DM than are FGAs or other SGAs. Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Diabetes & Antipsychotics: Possible Mechanisms Weight Gain Antipsychotics Diabetes Insulin resistance Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Diabetes & Antipsychotics: Monitoring Fasting glucose level or hemoglobin A1c Before starting a new antipsychotic: baseline levels. 3-4 months after. At least annually. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-72.

Antipsychotics & Dyslipidemia Increase of : Total cholesterol LDL TG levels Cholesterol Increase Antipsychotic High Clozapine Olanzapine Modest Risperidone Quetiapine Neutral Aripiprazole Ziprasidone Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-72.

Monitoring for Dyslipidemia Lipid profile at baseline If LDL level is normal (≤: 130mg/dl): lipid panel once every 2 years If LDL level is ˃ 130 mg/dl: lipid panel every 6 months Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-72.

Hyperprolactinemia

Tuberoinfundibular Pathway & Prolactin Release Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland. Dopamine tonically inhibits prolactin release. Physiology D2 antagonism increases prolactin levels. Implication

Tuberoinfundibular Pathway & Prolactin Release Antipsychotics increase prolactin by blocking D2 receptors in the tuberoinfundibular pathway

Hyperprolactinemia: Clinical Features Galactorrhea Amenorrhea Sexual dysfunction Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

Antipsychotics & Hyperprolactinemia Concerns of: Osteoporosis Breast cancer Common: FGAs Risperidone and paliperidone Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Cardiovascular Effects Orthostatic Hypotension QT prolongation

Orthostatic Hypotension

Orthostatic Hypotension Tachycardia Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Orthostatic Hypotension Alpha 1 blocking effects: Chlorpromazine, thioridazine Clozapine, olanzapine, risperidone Dose-related effect Can subside due to tolerance Start low, increase gradually Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Orthostatic Hypotension More dangerous in the elderly or medically ill patients. Chief danger: fainting or falling , injuries can produce significant morbidity. When appropriate: Check for history of orthostatic hypotension Warn patients Monitor BP (lying and standing) after the first dose and during first few days of treatment. Instruct patients to sit or stand up slowly Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

QT prolongation

Antipsychotics & QT prolongation QT prolongation can lead to torsades de pointes (can progress to ventricular fibrillation). More useful to refer to the corrected QT interval corrected (QTc). A QTc interval of 500 ms or greater is considered a risk factor for torsades de pointes. Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Antipsychotics & QT prolongation FGA Low potency Thioridazine Mesoridazine Chlorpromazine Pimozide SGA Ziprasidone Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Anticholinergic Effects

Anticholinergic Effects CNS Cognitive dysfunction Peripheral Autonomic Effects Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Peripheral Anticholinergic Effects Dry Mouth Blurred vision Constipation Urinary retention Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Antipsychotics with Anticholinergic Effects Chlorpromazine Clozapine Olanzapine Quetiapine Iloperidone Marder, S (2011). Pharmacotherapy for schizophrenia: Side effect management. In: Murray B Stein(Ed.), UpToDate.

Sedation Usually occurs during the first days of treatment. Some patients rapidly develop tolerance. Dose related effect. Can be useful early in treatment. Cause of poor treatment adherence. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

Sedation: Receptors Involved Histamine Acetylcholine Norepinephrine Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008

Sedation and Antipsychotic Potency Lower potency, higher sedation Sedating antipsychotics: clozapine, chlorpromazine and thioridazine. Risperidone, haloperidol and fluphenazine: more potent and less sedating. Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

Clinical Considerations Rapid discontinuation can lead to rebound insomnia Slow tapering Add other sedative medications (antihistamines) or hypnotics (benzodiazepines and non-benzodiazepines). Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Clozapine-Related Agranulocytosis ANC ˂ 500/mm3 WBC ˂ 2000/mm3 Potentially fatal condition Requires immediate medical attention

Clozapine-Related Agranulocytosis Before starting clozapine: WBC ≥ 3,500/ mm3 ANC ≥ 2,000/ mm3 Risk: Increases with age Higher in women Fever or any sign of infection is an immediate indication for WBC. If WBC ˂ 2000/mm3 or ANC ˂ 1000/mm3 : discontinue clozapine. http://www.clozaril.com/hcp/treating/wbc_anc.jsp

Monitoring for Clozapine-Related Agranulocytosis First 6 months: weekly monitoring (*) 6-12 months: every 2 weeks monitoring (*) After 12 months: monthly monitoring (*) (*) If WBC ≥ 3,500/ mm3 ANC ≥ 2,000/ mm3 http://www.clozaril.com/hcp/treating/wbc_anc.jsp

Seizure Threshold Antipsychotics tend to lower the seizure threshold. Usually not contraindicated in patients with seizure disorders but should be used with caution. Clozapine has a black box warning for this effect.

Hepatic Effects Severe hepatic effects are rare. Asymptomatic elevations of liver enzyme levels occur during the first 3 months of treatment. 0.1-0.5% of patients treated with chlorpromazine can develop cholestatic jaundice. Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

Skin & Eye Complications Chlorpromazine can cause: Pigmentation of skin areas exposed to light and pigment deposits in the eye. Photosensitivity Retinal pigmentation occurs only with thioridazine (serious irreversible effect above 800 mg/day). Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

References and Further Reading Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-72. Clozapine manufacturer prescribing information: http://www.clozaril.com/hcp/treating/wbc_anc.jsp Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008 Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010. Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010