1. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 31 Antipsychotic Agents and Their Use in Schizophrenia

2. 2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Antipsychotic Agents  Chemically diverse group of compounds  Used for diverse spectrum of psychotic disorders  Schizophrenia, delusional disorders, bipolar disorders, depressive psychoses, drug-induced psychoses  Also used to suppress emesis and to treat Tourette’s syndrome and Huntington’s chorea  Should not be used to treat dementia in the older adult

3. 3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Antipsychotic Agents  First-generation antipsychotics (FGAs) or conventional antipsychotics  Block receptors for dopamine in CNS  Cause serious movement disorders (extrapyramidal symptoms [EPS])  Second-generation antipsychotics (SGAs) or atypical antipsychotics  Produce only moderate blockade of dopamine receptors; stronger blockade for serotonin  Fewer EPS

4. 4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Antipsychotic Agents  Top-selling medications in the United States in 2009  Total sales of $14.6 billion  FGA higher risk of EPS  SGA higher risk of metabolic effects (diabetes, dyslipidemia)

5. 5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clinical Presentation  Disordered thinking and reduced ability to comprehend reality  Three types of symptoms  Positive symptoms and negative symptoms  Cognitive symptoms  Acute episodes  Residual symptoms  Long-term course  Causes

6. 6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Conventional Antipsychotic Agents I: Group Properties  Classification  Mechanism of action  Therapeutic uses  Adverse effects  Physical and psychologic dependence  Drug interactions  Toxicity

7. 7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Classification  Classification by potency  Low potency: chlorpromazine HCl (Thorazine)  Medium potency: loxapine (Loxitane)  High potency: haloperidol (Haldol)  Chemical classification  Six major chemical categories  Drugs in all groups equivalent with respect to antipsychotic actions

8. 8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Mechanism of Action  Conventional antipsychotic drugs block a variety of receptors within and outside the CNS  They block dopamine 2 (D 2 ) receptors in the mesolimbic area of the brain

9. 9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Therapeutic Uses  Schizophrenia  Bipolar disorder (manic-depressive illness)  Tourette’s syndrome  Prevention of emesis  Other applications

10. 10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adverse Effects  Extrapyramidal symptoms (EPS)  Acute dystonia  Parkinsonism  Akathisia  Tardive dyskinesia

11. 11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adverse Effects  Other adverse effects  Neuroleptic malignant syndrome Rare but serious reaction Rare but serious reaction Risk of death without treatment Risk of death without treatment Sweating, rigidity, sudden high fever, autonomic instability Sweating, rigidity, sudden high fever, autonomic instability  Anticholinergic effects See Table 31-3. See Table 31-3.  Orthostatic hypotension

12. 12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adverse Effects  Other adverse effects (cont’d)  Sedation  Neuroendocrine effects  Seizures  Sexual dysfunction  Dermatologic effects  Agranulocytosis  Severe dysrhythmias

13. 13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Physical and Psychologic Dependence  Development of physical and psychologic dependence is rare  Abrupt withdrawal of antipsychotics can precipitate a mild abstinence syndrome

14. 14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Interactions  Anticholinergic drugs  Intensify the anticholinergic effect  CNS depressants  Can intensify the depressant effect  Levodopa and direct dopamine receptor agonists  May counteract the antipsychotic effects of neuroleptics

15. 15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicity  Conventional antipsychotic drugs are very safe  Death by overdose is extremely rare  Overdose produces hypertension, CNS depression, and EPS  Treatment  Intravenous fluids, alpha-adrenergic agonist, gastric lavage  Emetics not effective: neuroleptics block the antiemetic action

16. 16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Conventional Antipsychotic Agents II: Individual Agents  Low-potency agents  Medium-potency agents  High-potency agents  Depot preparations

17. 17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Low-Potency Agents  Chlorpromazine (Thorazine)  Therapeutic uses  Pharmacokinetics  Adverse effects  Drug interactions  Preparations, dosage, and administration Oral therapy Oral therapy Parenteral therapy Parenteral therapy  Thioridazine (Mellaril)

18. 18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Medium-Potency Agents  Loxapine (Loxitane)  Molindone (Moban)  Perphenazine (Trilafon)

19. 19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. High-Potency Agents  Haloperidol (Haldol)  Actions and uses  Pharmacokinetics  Adverse effects  Preparations, dosage, and administration Oral therapy Oral therapy Intramuscular therapy Intramuscular therapy

20. 20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other High-Potency Agents  Fluphenazine (Prolixin)  Trifluoperazine (Stelazine)  Thiothixene (Navane)  Pimozide (Orap)

21. 21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Atypical Antipsychotic Agents  Introduced in the 1990s  Less risk of EPS than FGAs  Increased risk of weight gain, diabetes, and dyslipidemia  Examples: clozapine and other atypical antipsychotics

22. 22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clozapine  Mechanism of action  Blocks dopamine and serotonin  Therapeutic use  Schizophrenia  Levodopa-induced psychosis  Pharmacokinetics

23. 23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clozapine  Adverse effects and interactions  Agranulocytosis  Seizures  Diabetes  Weight gain  Myocarditis  Effects in older adult patients with dementia About double the mortality rate About double the mortality rate  Drug interactions  Preparations, dosage, and administration

24. 24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antipsychotics  Risperidone (Risperdal)  Mechanism of action Binds to multiple receptors Binds to multiple receptors  Pharmacokinetics  Therapeutic effects  Adverse effects Generally infrequent and mild Generally infrequent and mild  Preparations, dosage, and administration Schizophrenia, oral therapy Schizophrenia, oral therapy Schizophrenia, intramuscular therapy Schizophrenia, intramuscular therapy Bipolar disorder Bipolar disorder

25. 25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antipsychotics  Olanzapine (Zyprexa)  Mechanism of action Blocks 5-HT 2 receptors Blocks 5-HT 2 receptors Blocks D 2 receptors Blocks D 2 receptors  Pharmacokinetics  Therapeutic uses Schizophrenia Schizophrenia Bipolar disorder Bipolar disorder  Adverse effects

26. 26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antipsychotics  Olanzapine (Zyprexa) (cont’d)  Preparations, dosage, and administration Schizophrenia dosage Schizophrenia dosage  Oral dosage Bipolar disorder dosage Bipolar disorder dosage  Oral formulation

27. 27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antipsychotics  Quetiapine (Seroquel)  Actions and uses  Pharmacokinetics  Adverse effects  Drug interactions  Preparations, dosage, and administration Schizophrenia dosage Schizophrenia dosage Bipolar disorder dosage Bipolar disorder dosage

28. 28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antipsychotics  Ziprasidone (Geodon)  Mechanism of action Blocks multiple receptors: D 2, 5-HT 2, H 1 Blocks multiple receptors: D 2, 5-HT 2, H 1  Pharmacokinetics  Adverse effects  Drug interactions  Preparations, dosage, and administration Schizophrenia, intramuscular dosage Schizophrenia, intramuscular dosage Bipolar disorder (see Table 31-4) Bipolar disorder (see Table 31-4)

29. 29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antipsychotics  Aripiprazole (Abilify)  Contrasts with other atypical antipsychotic agents  Mechanism of action Blocks multiple receptor types Blocks multiple receptor types  Pharmacokinetics  Adverse effects  Drug interactions  Preparations, dosage, and administration Schizophrenia dosage Schizophrenia dosage Bipolar disorder dosage Bipolar disorder dosage

30. 30Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Depot Preparations  Depot antipsychotics: long-acting, injectable formulations used for long-term maintenance therapy of schizophrenia  No evidence that depot preparations pose an increased risk of side effects  Three depot preparations available  Haloperidol decanoate (Haldol Decanoate)  Fluphenazine decanoate (Prolixin Decanoate)  Risperidone microspheres (Risperdal Consta)

31. 31Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Drug Therapy  Three major objectives  Suppression of acute episodes  Prevention of acute exacerbations  Maintenance of the highest possible level of functioning  Drug selection  Dosing  Route  Oral (tablets, capsules, liquids)  Intramuscular

32. 32Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Drug Therapy  Most FGAs and SGAs are equally effective, except for clozapine, which is more effective than the rest  FGAs: significant risk of EPS  SGAs: risk of metabolic effects  FGAs: cost 10 times less than SGAs

33. 33Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Drug Therapy  Dosing  Highly individualized  Older adult patients require relatively small doses.  Size and timing likely to be changed over course of therapy  Routes  Oral (preferred)  Intramuscular

34. 34Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Drug Therapy  Initial therapy  Maintenance therapy  Adjunctive drugs  Benzodiazepines  Antidepressants

35. 35Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Drug Therapy  Promoting adherence  Ensure that the medication is taken  Encourage family members to oversee medication for outpatients  Provide patients with instructions  Inform patients and their families that antipsychotics must be taken on a regular schedule

36. 36Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Drug Therapy  Promoting adherence (cont’d)  Inform patients about side effects of treatment  Assure patients that antipsychotic drug use does not lead to addiction  Establish a good therapeutic relationship with patient  Use an intramuscular depot preparation for long- term therapy

37. 37Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Schizophrenia Nondrug Therapy  Counseling for patient and family  Behavioral therapy  Vocational training