1. ANTIPSYCHOTIC MEDICATIONS Presented By: Jocelyn Aquino M.D.

3. Introduction of conventional antipsychotics - Synthesis of Chlorpromazine in 1950 - First clinical trial of Chlorpromazine for agitation and psychosis by Deniker, et al in 1952 - Classified as: Phenothiazines (Clorpromazine) Piperazines (Perphenazine, Fluphenazine, Trifluroperazine) Piperidines (Thioridazine, Mesoridazine) Thioxanthenes (Thiothixine) Butyrophenones (Haloperidol) Dihydroindolines (Molindone) Diphenylbutylpiperidines (Pimozide)

4. Typical Antipsychotic

6. Mechanism of Action: Blockade of D2 receptors Mesolimbic Overactivity = Positive Symptoms of Psychosis

7. Mesolimbic Pathway Blocked = Diminished Positive Psychotic Symptoms

9. List and Characteristics of Conventional Antipsychotics

12. ExtraPyramidal Symptoms - Acute Dystonic Reactions with tightening of facial and neck muscles, associated torticollis or retrotorticollis, with or without tightness in the jaw - Akathisia described as “restless legs” or the “need to keep moving” - Parkinsonism characterized as flattening of the facial expressions, stiffness of gait, muscular rigidity in the trunk and extremities, pill rolling tremor of the fingers, and at times excessive salivation Tardive Dyskinesia chronic and often debilitating rhythmic, choreoathetoic movements, incidence is about 25% in patients taking antipsychotic agents for 2 years, 50% of cases are irreversible, 5-10x greater risk in older patients

13. Atypical Antipsychotic

14. Mechanism Of Action Of Atypical Antipsychotics - Blockade of D2 receptors - Serotonin dopamine antagonist - D4 receptor antagonist - D1 receptor antagonist - Dopamine partial agonist - 5HT3 receptor antagonist - 5HT2C antagonist - 5HT/NE neuronal reuptake

15. Subcortical region - increase dopamine activity = positive symptoms Frontal cortex - low dopamine activity = negative symptoms

16. Correlation Between Pharmacologic Profile And Adverse Side Effects

17. Relative Advantages of Atypical Antipsychotics: - Fewer EPS due to blockade of D2 receptors and other receptors - Incidence of TD is improved - Improvement of negative symptoms - Possible improvement of cognitive symptoms - Not need augmentation with anticholinergics - Efficacy for mood and suicidality (Clozapine) - Efficacy for treatment-resistant patients (Clozapine) - Decrease relapse Disadvantage of Atypical Antipsychotics: - Relatively more expensive - Association with increased metabolic and cardiovascular risk

18. Factors to Consider in Selecting Which Medication to Prescribe: (The Risk Benefit Analysis Ratio) Patient related factors: - Prior history of similar episodes - Previous psychotropic drug treatment - Favorable and adverse response to any psychotropic medications - Patient’s preference for a particular medication based on past experience - Any medical condition or recent treatment with medications for non-psychiatric illnesses - Past and present alcohol history - Use of over-the-counter or illicit drugs - Complexity of illness - Co-morbidities –psychiatric and medical - Illness burden - Functional disability

19. Drug Related Factors: - FDA indications - Adverse side effects - Pharmacokinetic properties - Drug to drug interactions - Cost - Intended route of administration Most patients prefer oral medication. Patient with recurrent relapse related to non-adherence are candidates for long acting injectable antipsychotic medication.

20. Assumptions: - All are equal in efficacy when dose is optimal. - Each have a unique SE profile. - Each have a unique pharmacokinetic properties. - Individual patients responds preferentially to certain medication. - No patient characteristics predict response to a particular medication

23. Olanzapine (Zyprexa):Dose 10-30mg/d Advantages: - Wide range of receptor activity - Half-life is 30 hours - 5 hours to peak - Available in disintegrating tablets (dissolves quickly, difficult to cheek or spit out, comparable to intramuscular injection, certainty of dosage) - Injectable form 10mg vial (10mg/injection) Disadvantages: - Risk of weight gain - Associated with diabetes and metabolic dyscontrol - Sedation - Orthostatic - Anticholinegic effects

24. Quetiapine (Seroquel): Dose 100 -300 to 400-800mg/d Advantages: - Short elimination half-life (6 hours) given twice a day dose, works also once a day dose - Lowest incidence of EPS - Useful for psychosis in Parkinson’s Disease - Rapid onset of action Disadvantages: - Only in tablet form - More expensive - Higher level of sedation even with gradual titration - Orthostatic SE during early phase of treatment - Risk of weight gain - Akathisia - Anticholinergic effects - Carries warning about potential development of cataracts

27. Aripiprazole (Abilify): Dose 10-15mg up to 30mg/d Advantages: - Partial agonist at dopamine and serotonin receptors (binds and activates but not same extent as a full agonist) - 5HT1A receptor agonist activity - 75 hours elimination half life - Intermediate peak concentration - Relatively low incidence of EPS - Recent indication for Bipolar patients - Injectable IM 10 and 15mg Disadvantages: - SE: nausea, vomiting, insomnia, headache - Not a lot of clinical experience

28. Selected Side Effects Of Commonly Used Antipsychotic Medications

29. Pharmacologic Profile Of Some Antipsychotics

31. Medical Comorbilities - Diabetes and Obesity is reported to be 1.5 - 2 times higher in people with Affective Disorders and Schizophrenia compared with the general population. - People with chronic mental illness have increased morbidity and mortality from natural causes compared with the general population. - They have 15% to 20% lower life expectancy. Characteristics of Individuals with Chronic Mental Illness - Medically underserved - Sedentary behavior - Excessive sleeping - Overeating - Poor Nutrition - Substance Abuse (47%) - Smoking (75% vs 25%)

32. Based on Consensus Statement, Diabetes Care 2004 Feb:27 (2) 596-601

33. Source: Based on Toalson Pet al Primary Care Companion Journal of Clinical Psychiatry 2004;6:152-158

34. From the American Diabetic Association, American Psychiatric Association, American Association of Clinical Endocrinologist and the North American Association for the study of Obesity Source: Based on consensus statement, Diabetic Care 2004 Feb 27 (2); 596-601

35. Increased Mortality In Elderly Patients With Dementia Related Psychosis : Elderly patients with dementia related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analysis of 17 placebo controlled trials (modal duration of 10 weeks) in this patients revealed a risk of death in the drug treated patients of between 1.6 to 1.7 times seen in placebo treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug treated patients was about 4.5% compared to a rate of 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature.

36. Neurleptic Malignant Syndrome - life threatening, occurs in about 0.5%-1% of patients treated with antipsychotic, more frequent in conventional high potency agents, occurs in atypicals as well. Cardinal Signs and Symptoms - include body temperature exceeding 38*C, altered level of consciousness, tachycardia, labile blood pressure, diaphoresis and extreme muscle rigidity Elevated CPK > 300U/ml, Elevated WBC>15,000/mm3 Treatment - discontinuation of antipsychotics and supportive

37. Choice Of Medication In The Acute Phase Of Schizophrenia

38. Antipsychotic Algorhythm

45. Antipsychotic Drug Interactions:

46. Addition of inhibitors of CYP3A4 and 1A2 isozymes such as erythromycin and fluvoxamine can elevate clozapine serum concentration to toxic levels. Carbamazepine, phenobarbital and phenytoin – induce metabolism of antipsychotic agents , thereby lowering serum concentrations below a therapeutic threshold.

51. References: - APA Practice Guideline for Treatment of Psychiatric Disorders Compendium 2004 - Essentials of Clinical Psychiatry 2004 - Handbook of Drug Therapy in Psychiatry 3 rd edition - Practical Guide to Care of Psychiatric Patients 3 rd edition - Essential Psychopharmacology Neuroscientific Basis and Practical Applications by Stephen M. Stahl - Medical Comorbidity in Patients with Schizophrenia, Journal of Clinical Psychiatry Supplement 6 Vol 66, Nasrallah,Keck 2005 - New Findings in Schizophrenia: An Update on Causes and Treatment, Supplement to Clinical Psychiatry News, Nemeroff, Lieberman et al 2004 Other resources: APA Practice Guideline http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm

52. VERSION: Edited: 02112006