1. Clinical pharmacology of antipsychotic agents
Domina Petric, MD

2. Indications I.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Psychiatric indications
Schizophrenia
Catatonic schizophrenia
Schizoaffective disorders
Bipolar affective disorder
Tourette´s syndrome
Alzheimer´s disease
Psychotic depression
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Schizophrenia is the primary indication for antipsychotic agents.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Schizophrenia
Catatonic forms of schizophrenia are best managed by intravenous benzodiazepines.
Antipsychotic drugs may be needed to treat psychotic components of that form of the illness after catatonia has ended.
Many patients show little response and virtually none of the patients showed a complete response.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Emedicinahealth.net
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Schizoaffective disorders
Schizoaffective disorders share characteristics of both schizophrenia and affective disorders.
The psychotic aspects of the illness require treatment with antipsychotic drugs.
Antidepressants, lithium or valproic acid may be helpful for the affective component.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Bipolar affective disorder
The manic phase in bipolar affective disorder (BAD) often requires treatment with antipsychotic agents.
Lithium or valproic acid supplemented with high-potency benzodiazepines (lorazepam, clonazepam) may suffice in milder cases.
There are evidences for efficacy of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Bipolar affective disorder
Aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone have been approved for the treatment of various phases of bipolar disorder: most effective for the manic phase and for maintenance treatment.
As mania subsides, the antipsychotic drug may be withdrawn or used for maintenance treatment.
Nonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepines.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Other indications Tourette´s syndrome
Disturbed behavior in patients with Alzheimer´s disease
Psychotic depression in combination with antidepressants
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. WRONG INDICATIONS
Antipsychotics are not indicated for the treatment of various withdrawal syndromes!
In small doses, antipsychotics have been wrongly promoted for the relief of anxiety associated with minor emotional disorders: antianxiety sedatives are preferred!
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Psychiatric indications
Schizophrenia
Catatonic forms: in combination with intravenous benzodiazepines
Primary indication
Schizoaffective disorders
For the treatment of psychotic aspects
Psychosis
Bipolar disorder
Mania
For the treatment of mania and maintenance therapy
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. Nonpsychiatric indications
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Nonpsychiatric indications
Antiemesis
Most older typical antipsychotic drugs, with the exception of thioridazine, have a strong antiemetic effect.
This action is due to dopamine-receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach).
Prochlorperazine and benzquinamide are promoted solely as antiemetics.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Nonpsychiatric indications
Phenotiazines with shorter side chains have considerable H1 receptor-blocking action.
These agents have been used for relief of pruritus.
Promethazine has been used as preoperative sedative.
The butyrophenone droperidol is used in combination with an opioid fentanyl in neuroleptanesthesia.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

16. Drug choice
II.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

17. Clozapine Olanzapine Quetiapine Advantages Disadvantages Thioridazine
Drug class
Drug
Advantages
Disadvantages
Phenothiazines
Aliphatic
Chlorpromazine
Generic, inexpensive
Many adverse effects, especially autonomic
Piperidine
Thioridazine
Slight extrapyramidal syndrome (EPS), generic
800 mg/d limit, no parenteral form, cardiotoxicity
Piperazine
Fluphenazine
Depot form also available (enanthate, decanoate)
Increased tardive dyskinesia
Thioxanthene
Thiothixene
Parenteral form also available, decreased tardive dyskinesia
Uncertain
Butyrophenone
Haloperidol
Parenteral form also available, generic
Severe EPS
Dibenzoxazepine
Loxapine
No weight gain
Dibenzodiazepine
Clozapine
For treatment-resistant patients, little EPS
Agranulocytosis (2%), dose-related lowering of seizure treshold
Benzisoxazole
Risperidone
Broad efficacy, little or no EPS at low doses
EPS and hypotension in higher doses
Thienobenzodiazepine
Olanzapine
Effective against negative as well as positive symptoms, little or no EPS
Weight gain, dose-related lowering of seizure treshold
Dibenzothiazepine
Quetiapine
Similar to olanzapine, perhaps less weight gain
May require high doses if there is associated hypotension, short t1/2 and twice daily dosing
Dihydroindolone
Ziprasidone
Less weight gain than clozapine, parenteral form available
QTc prolongation
Dihydrocarbostyril
Aripiprazole
Lower weight gain liability, long half-life, novel mechanism potential
Uncertain, novel toxicities possible
Katzung, Masters, Trevor. Basic and clinical pharmacology.

18. Both typical and atypical antipsychotics
Drug choice
Both typical and atypical antipsychotics
Atypical drugs
For approximately 70% of patients with schizophrenia and bipolar disorder with psychotic features may be treated with equal efficacy with both typical and atypical antipsychotics when it comes to POSITIVE symptoms.
Negative symptoms are better treated with atypical antipsychotics.
Atypical drugs have diminished risk of tardive dyskinesia and other forms of EPS.
They increase prolactine levels to lesser extent.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

19. Drug choice
A small percentage of patients develop diabetes mellitus, most often with CLOZAPINE and OLANZAPINE.
Ziprasidone is causing the least weight gain.
Risperidone, paliperidone and aripiprazole usually produce small increases in weight and lipids, whilst asenapine and quetiapine have an intermediate effect.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

20. Drug choice
Clozapine and olanzapine frequently result in large increases in weight and lipids.
These drugs should be considered as second-line drugs unless there is a specific indication.
Clozapine at high doses ( mg/day) is effective in the majority of patients with schizophrenia refractory to other drugs.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

21. Drug choice
High dose olanzapine, mg/day, may be efficacious in refractory shizophrenia when given over a six month period.
Clozapine is the only atypical antipsychotic drug indicated to reduce the risk of suicide.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

22. Drug choice
New antipsychotic drugs have been shown more effective than older ones for treating negative symptoms.
New antipsychotics have superior adverse-effect profile and low to absent risk of tardive dyskinesia: first line treatment for all schizophrenic patients?
Katzung, Masters, Trevor. Basic and clinical pharmacology.

23. Drug choice
The best guide for selecting a drug for an individual patient is the patient´s past responses to drug.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

24. Dosage
III.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

25. Minimum effective therapeutic dose Usual range of daily doses
Drug
Minimum effective therapeutic dose
Usual range of daily doses
Chlorpromazine
100 mg mg
Thioridazine mg
Perphenazine
10 mg
8-64 mg
Trifluoperazine
5 mg
5-60 mg
Fluphenazine
2 mg
2-60 mg
Thiothixene
2-120 mg
Haloperidol
Loxapine mg
Molindone mg
Clozapine
50 mg mg
Olanzapine
10-30 mg
Quetiapine
150 mg mg
Risperidone
4 mg
4-16 mg
Ziprasidone
40 mg mg
Aripiprazole
Katzung, Masters, Trevor. Basic and clinical pharmacology.

26. Dosage
Patients who have become refractory to 2 or 3 antipsychotic agents given in substantial doses are candidates for treatment with clozapine or high-dose olanzapine.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

27. Parenteral preparations
IV.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

28. Parenteral preparations
Well-tolerated parenteral forms of the high-potency older drugs haloperidol and fluphenazine are available for rapid initiation of treatment as well as for maintenance treatment in noncompliant patients.
Parenterally administered drugs have much greater bioavailability than the oral forms: doses are only of fraction of that given orally.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

29. Parenteral preparations
Fluphenazine decanoate and haloperidol decanoate are suitable for long-term parenteral maintenance therapy in patients who can not or will not take oral medication.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

30. Dosage schedules V.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

31. Dosage schedules
Antipsychotic drugs are often given in divided daily doses, titrating to an effective dosage.
The low end of the dosage range should be tried for at least several weeks.
After an effective daily dosage has been defined for an individual patient, doses can be given less frequently.
Once-daily doses, usually given at night, are feasible for many patients during chronic maintenance treatment.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

32. Simplification of dosage schedules leads to better compliance.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

33. Maintenance treatment
VI.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

34. Maintenance treatment
A very small minority of schizophrenic patients may recover from an acute episode and require no further drug therapy for prolonged periods.
The choice is between increased doses or the addition of other drugs for exacerbations versus continual maintenance treatment with full therapeutic dosage.
The choice depends on social factors: availability of family or friends.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

35. Drug combinations
VII.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

36. Drug combinations
Tricyclic antidepressants or, more often, selective serotonin reuptake inhibitors (SSRIs) are often used with antipsychotic agents for symptoms of depression complicating schizophrenia.
Electroconvulsive therapy (ECT) is a useful adjunct for antipsychotic drugs: treatment of mood symptoms and for positive symptoms control.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

37. Drug combinations
ECT therapy can augment clozapine effect when maximum doses of clozapine are ineffective.
Adding risperidone to clozapine is not beneficial.
Lithium, valproic acid or lamotrigine is sometimes added to antipsychotic agents with benefit to patients who do not respond to the antipsychotics alone.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

38. Drug combinations
Benzodiazepines may be useful for patients with anxiety symptoms or insomnia not controlled by antipsychotics.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

39. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.
Emedicinahealth.net
Katzung, Masters, Trevor. Basic and clinical pharmacology.