1. Antipsychotic Agents and Their Use in Schizophrenia1

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 2

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 3

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) 4

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 5

6. Conventional Antipsychotic Agents I: Group Properties
Classification
Mechanism of action
Therapeutic uses
Adverse effects
Physical and psychologic dependence
Drug interactions
Toxicity 6

7. Classification Classification by potency Chemical classification
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 7

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 8

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

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

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 11

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

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

14. Drug Interactions Anticholinergic drugs CNS depressants
Intensify the anticholinergic effect
CNS depressants
Can intensify the depressant effect
Levodopa and direct dopamine receptor agonists
May counteract the antipsychotic effects of neuroleptics 14

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 15

16. Conventional Antipsychotic Agents II: Individual Agents
Low-potency agents
Medium-potency agents
High-potency agents
Depot preparations 16

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

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

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

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

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 21

22. Clozapine Mechanism of action Therapeutic use Pharmacokinetics
Blocks dopamine and serotonin
Therapeutic use
Schizophrenia
Levodopa-induced psychosis
Pharmacokinetics 22

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 23

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 24

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

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

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

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) 28

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 29

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) 30

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 31

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 32

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 33

34. Schizophrenia Drug Therapy
Initial therapy
Maintenance therapy
Adjunctive drugs
Benzodiazepines
Antidepressants 34

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 35

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 36

37. Schizophrenia Nondrug Therapy
Counseling for patient and family
Behavioral therapy
Vocational training 37