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  1. 1. ANTIPSYCHOTIC MEDICATIONS Presented By: Jocelyn Aquino M.D.
  2. 2. <ul><li>Uses of Antipsychotic Drugs: </li></ul><ul><li>Schizophrenia - acute treatment and prophylaxis </li></ul><ul><li>Schizoaffective Disorder - acute treatment and prophylaxis </li></ul><ul><li>Schizophreniform Disorder and Brief Psychotic disorder – acute treatment </li></ul><ul><li>Mania - acute treatment, maintenance </li></ul><ul><li>Psychotic depression - acute treatment and sometimes prophylaxis </li></ul><ul><li>Dementia - acute treatment, prophylaxis of recurrent psychosis </li></ul><ul><li>Drug - induced psychosis-acute short term treatment </li></ul><ul><li>Tourette’s Disorder </li></ul><ul><li>Violence and Agitation </li></ul><ul><li>OCD and severe anxiety unresponsive to other agents </li></ul>
  3. 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. 4. Typical Antipsychotic
  5. 6. Mechanism of Action: Blockade of D2 receptors Mesolimbic Overactivity = Positive Symptoms of Psychosis
  6. 7. Mesolimbic Pathway Blocked = Diminished Positive Psychotic Symptoms
  7. 9. List and Characteristics of Conventional Antipsychotics
  8. 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
  9. 13. Atypical Antipsychotic
  10. 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
  11. 15. Subcortical region - increase dopamine activity = positive symptoms Frontal cortex - low dopamine activity = negative symptoms
  12. 16. Correlation Between Pharmacologic Profile And Adverse Side Effects
  13. 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
  14. 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
  15. 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.
  16. 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
  17. 21. <ul><li>Clozapine(Clozaril): Dose 150-450mg/d up to 900mg/d </li></ul><ul><li>Advantages : </li></ul><ul><li>- Wide range of receptor activity at dopaminergic, serotonergic, adrenergic, histaminergic and cholinergic pathways </li></ul><ul><li>- Half life = 12 hours </li></ul><ul><li>30% of treatment resistant schizophrenia responded </li></ul><ul><li>Lowest incidence of EPS, little or no risk of TD </li></ul><ul><li>Efficacy in suicidality (24% reduction in suicidal risk) </li></ul><ul><li>Reduction of hostility and aggression in treatment resistant patients </li></ul><ul><li>Disadvantages: </li></ul><ul><li>- Potential lethal SE agranulocytosis (0.5%-1%) </li></ul><ul><li>- May cause seizures at high doses (2%), myocarditis (rare) </li></ul><ul><li>- Mandatory weekly blood counts initiating to treatment </li></ul><ul><li>- Need to titrate to therapeutic dose </li></ul><ul><li>- High cost </li></ul><ul><li>- Sedation particularly in early stages </li></ul><ul><li>- Sialorrhea </li></ul><ul><li>- Weight gain and metabolic abnormalities </li></ul>
  18. 22. <ul><li>Risperidone (Risperdal) Dose 2-6 mg/d: </li></ul><ul><li>Advantages </li></ul><ul><li>- Clinical experience </li></ul><ul><li>- Wide range of receptor activity </li></ul><ul><li>- Less anticholinergic activity </li></ul><ul><li>- 24 hour elimination half life </li></ul><ul><li>- 1 to 1.5 hour to peak </li></ul><ul><li>- Comes in disintegrating tab/liquid form </li></ul><ul><li>- Depo form Risperdal Consta dose 25-75mg every 2 weeks </li></ul><ul><li>Haldol/Prolixin depo has side effects associated </li></ul><ul><li>with peak concentration </li></ul><ul><li>Absorption in the GI tract </li></ul><ul><li>   </li></ul><ul><li>Disadvantages </li></ul><ul><li>- Sedation </li></ul><ul><li>- Hyperprolactinemia rare (galactorrhea, breast swelling, menstrual irregularities,impaired sexual functioning) </li></ul><ul><li>- Risk of weight gain </li></ul><ul><li>- Dose dependent EPS 6-8mg/d </li></ul>
  19. 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
  20. 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
  21. 25. <ul><li>Ziprasidone (Geodon): Dose 80-120 to 120-160mg/d </li></ul><ul><li>Advantages: </li></ul><ul><li>- Wide range receptor activity and has partial agonist activity at 5HT1a receptors </li></ul><ul><li>- 5HT2 NE reuptake inhibitor </li></ul><ul><li>- ?Advantage in affective disorder </li></ul><ul><li>- Half life = 7 hours </li></ul><ul><li>- Less weight gain and metabolic abnormalities </li></ul><ul><li>- Low risk of sexual SE </li></ul><ul><li>- Low cost - all pills are priced the same way </li></ul><ul><li>1st drug to become injectable for acute agitation 20mg vial </li></ul><ul><li>(10 - 20mg per injection, given every 2 - 4 hours to maximum of 40 mg/day) </li></ul><ul><li>Disadvantages: </li></ul><ul><li>- Slow to get peak concentration </li></ul><ul><li>- Not as effective on low doses </li></ul><ul><li>- Higher level of EPS on quick titration </li></ul><ul><li>- Given BID dose </li></ul><ul><li>- QTc prolongation - not clinically significant, no cases of sudden death, less compared to Mellaril </li></ul><ul><li>- Packaged insert contains warning not to be used with other drugs </li></ul><ul><li>that prolong QTc, history of long QTc syndrome, history of cardiac arrhytmias, QTc >500msec, recent acute MI, or uncompensated heart failure </li></ul>
  22. 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
  23. 28. Selected Side Effects Of Commonly Used Antipsychotic Medications
  24. 29. Pharmacologic Profile Of Some Antipsychotics
  25. 30. <ul><li>Highlights: </li></ul><ul><li>  </li></ul><ul><li>Dose dependent EPS for high doses – </li></ul><ul><li>Risperidone, Olanzapine, FGA </li></ul><ul><li>Hyperprolactenemia – Risperidone, FGA </li></ul><ul><li>QTc prolongation – Ziprazidone, Thioridazine </li></ul><ul><li>Anticholinergic - Olanzapine, Clozapine </li></ul><ul><li>Orthostatic - Quetiapine </li></ul><ul><li>Weight gain - Clozapine, Olanzapine (7% or more) </li></ul>
  26. 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%)
  27. 32. Based on Consensus Statement, Diabetes Care 2004 Feb:27 (2) 596-601
  28. 33. Source: Based on Toalson Pet al Primary Care Companion Journal of Clinical Psychiatry 2004;6:152-158
  29. 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
  30. 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.
  31. 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
  32. 37. Choice Of Medication In The Acute Phase Of Schizophrenia
  33. 38. Antipsychotic Algorhythm
  34. 39. <ul><li>Course of Schizophrenia: </li></ul><ul><li>15% meet symptom remission </li></ul><ul><li>25% had adequate social functioning for 2 years or more </li></ul><ul><li>About 25% will relapse within 1 year with treatment </li></ul><ul><li>- 87% relapse by the fifth year </li></ul><ul><li>Lower rate of relapse with treatment </li></ul><ul><li>Continuous treatment appears to be more effective than intermittent treatment of emergent symptoms in preventing relapse </li></ul><ul><li>- Positive symptoms - episodic </li></ul><ul><li>- Negative symptoms - begin earlier, pre-morbid symptoms, likely not to go back to baseline </li></ul><ul><li>Cognitive symptoms - worsens after acute episodes </li></ul><ul><li>(2 standard deviation below normal after first episode) </li></ul>Goals of Treatment: - Reduce acute symptoms - Improve long term course - Avoid relapse
  35. 40. Areas Of Neurocognitive Dysfunction In Schizophrenia <ul><li>- Verbal and learning memory </li></ul><ul><li>- Speed of processing </li></ul><ul><li>- Working memory </li></ul><ul><li>- Reasoning and problem solving </li></ul><ul><li>- Attention and vigilance </li></ul><ul><li>- Visual learning and memory </li></ul><ul><li>- Social learning </li></ul>
  36. 41. Improvement In Cognition <ul><li>- Better work function </li></ul><ul><li>- Better social function </li></ul><ul><li>- Better social skills </li></ul><ul><li>- Better coping skills </li></ul><ul><li>- Better quality of life </li></ul><ul><li>- Hope </li></ul>
  37. 42. Psychosocial Interventions <ul><li>Rehabilitative therapy </li></ul><ul><li>Supported employment </li></ul><ul><li>Case Management </li></ul><ul><li>Prevention of co-morbid substance abuse </li></ul><ul><li>Family Interventions </li></ul>
  38. 43. Chemical Targets For Cognitive Therapy <ul><li>- Nicotinic receptor in the hippocampus </li></ul><ul><li>- Dopamine receptor in the pre-frontal cortex </li></ul><ul><li>- 5HT2A receptor in the frontal cortex </li></ul><ul><li>- Noradrenergic receptor in the pre-frontal cortex </li></ul><ul><li>- Glutaminergic enhancer </li></ul><ul><li>- Muscarinic agonist </li></ul>
  39. 45. Antipsychotic Drug Interactions:
  40. 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.
  41. 48. <ul><li>Outcome Assessment </li></ul><ul><li>- Mortality and Morbidity Risk </li></ul><ul><li>- Re-hospitalization and relapse rate </li></ul><ul><li>Quality of life for patients and their families </li></ul><ul><li>Drug Cost Acquisition </li></ul><ul><li>Employment versus unemployment </li></ul><ul><li>- Utilization of Outpatient care resources </li></ul><ul><li>Public safety </li></ul>
  42. 49. Summary <ul><li>Typical and Atypical Antipsychotics are equally effective in reducing positive symptoms in Schizophrenia. </li></ul><ul><li>Atypical Antipsychotics </li></ul><ul><li>Efficacy in positive and negative symptoms </li></ul><ul><li>Possible efficacy in cognitive symptoms </li></ul><ul><li>Less EPS side effect profile </li></ul><ul><li>Relatively more expensive </li></ul><ul><li>Associated with cardiovascular and metabolic risk </li></ul>
  43. 50. <ul><li>Antipsychotic medications are an important component in the treatment of many psychotic conditions </li></ul><ul><li>Adverse effect profiles differ among typical and atypical agents </li></ul><ul><li>Clinicians should be aware of these issues with patient monitoring </li></ul><ul><li>Treatment should be individualized </li></ul><ul><li>Careful selection of appropriate psychotropic agent is critical to maximize efficacy while avoiding adverse side effects or worsening of the patient’s comorbid medical condition. </li></ul><ul><li>More studies are needed to develop newer antipsychotic medications with less adverse side effects for the effective treatment of global psychopathology of Schizophrenia </li></ul>Conclusion
  44. 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
  45. 52. VERSION: Edited: 02112006