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Chapter 31

Chapter 31. Antipsychotic Agents and Their Use in Schizophrenia. Antipsychotic Agents. Chemically diverse group of compounds Used for diverse spectrum of psychotic disorders Schizophrenia, delusional disorders, bipolar disorders, depressive psychoses, drug-induced psychoses

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Chapter 31

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  1. Chapter 31 Antipsychotic Agents and Their Use in Schizophrenia

  2. 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. 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. 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. 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. Conventional Antipsychotic Agents I: Group Properties • Classification • Mechanism of action • Therapeutic uses • Adverse effects • Physical and psychologic dependence • Drug interactions • Toxicity

  7. 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. Mechanism of Action • Conventional antipsychotic drugs block a variety of receptors within and outside the CNS • They block dopamine2 (D2) receptors in the mesolimbic area of the brain

  9. Therapeutic Uses • Schizophrenia • Bipolar disorder (manic-depressive illness) • Tourette’s syndrome • Prevention of emesis • Other applications

  10. Adverse Effects • Extrapyramidal symptoms (EPS) • Acute dystonia • Parkinsonism • Akathisia • Tardive dyskinesia

  11. Adverse Effects • Other adverse effects • Neuroleptic malignant syndrome • Rare but serious reaction • Risk of death without treatment • Sweating, rigidity, sudden high fever, autonomic instability • Anticholinergic effects • See Table 31-3. • Orthostatic hypotension

  12. Adverse Effects • Other adverse effects (cont’d) • Sedation • Neuroendocrine effects • Seizures • Sexual dysfunction • Dermatologic effects • Agranulocytosis • Severe dysrhythmias

  13. Physical and Psychologic Dependence • Development of physical and psychologic dependence is rare • Abrupt withdrawal of antipsychotics can precipitate a mild abstinence syndrome

  14. 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. 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. Conventional Antipsychotic Agents II: Individual Agents • Low-potency agents • Medium-potency agents • High-potency agents • Depot preparations

  17. Low-Potency Agents • Chlorpromazine (Thorazine) • Therapeutic uses • Pharmacokinetics • Adverse effects • Drug interactions • Preparations, dosage, and administration • Oral therapy • Parenteral therapy • Thioridazine (Mellaril)

  18. Medium-Potency Agents • Loxapine (Loxitane) • Molindone (Moban) • Perphenazine (Trilafon)

  19. High-Potency Agents • Haloperidol (Haldol) • Actions and uses • Pharmacokinetics • Adverse effects • Preparations, dosage, and administration • Oral therapy • Intramuscular therapy

  20. Other High-Potency Agents • Fluphenazine (Prolixin) • Trifluoperazine (Stelazine) • Thiothixene (Navane) • Pimozide (Orap)

  21. 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. Clozapine • Mechanism of action • Blocks dopamine and serotonin • Therapeutic use • Schizophrenia • Levodopa-induced psychosis • Pharmacokinetics

  23. Clozapine • Adverse effects and interactions • Agranulocytosis • Seizures • Diabetes • Weight gain • Myocarditis • Effects in older adult patients with dementia • About double the mortality rate • Drug interactions • Preparations, dosage, and administration

  24. Other Atypical Antipsychotics • Risperidone (Risperdal) • Mechanism of action • Binds to multiple receptors • Pharmacokinetics • Therapeutic effects • Adverse effects • Generally infrequent and mild • Preparations, dosage, and administration • Schizophrenia, oral therapy • Schizophrenia, intramuscular therapy • Bipolar disorder

  25. Other Atypical Antipsychotics • Olanzapine (Zyprexa) • Mechanism of action • Blocks 5-HT2 receptors • Blocks D2 receptors • Pharmacokinetics • Therapeutic uses • Schizophrenia • Bipolar disorder • Adverse effects

  26. Other Atypical Antipsychotics • Olanzapine (Zyprexa) (cont’d) • Preparations, dosage, and administration • Schizophrenia dosage • Oral dosage • Bipolar disorder dosage • Oral formulation

  27. Other Atypical Antipsychotics • Quetiapine (Seroquel) • Actions and uses • Pharmacokinetics • Adverse effects • Drug interactions • Preparations, dosage, and administration • Schizophrenia dosage • Bipolar disorder dosage

  28. Other Atypical Antipsychotics • Ziprasidone (Geodon) • Mechanism of action • Blocks multiple receptors: D2, 5-HT2, H1 • Pharmacokinetics • Adverse effects • Drug interactions • Preparations, dosage, and administration • Schizophrenia, intramuscular dosage • Bipolar disorder (see Table 31-4)

  29. Other Atypical Antipsychotics • Aripiprazole (Abilify) • Contrasts with other atypical antipsychotic agents • Mechanism of action • Blocks multiple receptor types • Pharmacokinetics • Adverse effects • Drug interactions • Preparations, dosage, and administration • Schizophrenia dosage • Bipolar disorder dosage

  30. 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. 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. 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. 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. Schizophrenia Drug Therapy • Initial therapy • Maintenance therapy • Adjunctive drugs • Benzodiazepines • Antidepressants

  35. 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. 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. Schizophrenia Nondrug Therapy • Counseling for patient and family • Behavioral therapy • Vocational training

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