Clinical pharmacology of antipsychotic agents: indications, dosage, maintenance therapy

1. Clinical pharmacology of
antipsychotic agents
Domina Petric, MD

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

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

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

5. • 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
Schizophrenia

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

7. • 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
Schizoaffective disorders

8. • 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
Bipolar affective disorder

9. • 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withdrawn or used for maintenance treatment.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
Bipolar affective disorder

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

11. • 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
WRONG INDICATIONS

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

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

14. 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
Nonpsychiatric indications

15. • 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
Nonpsychiatric indications

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

17. Katzung, Masters, Trevor.
Basic and clinical
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 Uncertain
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

18. Both typical and atypical
antipsychotics
• 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.
Atypical drugs
• 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
Drug choice

19. • 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
Drug choice

20. • 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 (300-900 mg/day) is
effective in the majority of patients with
schizophrenia refractory to other drugs.
Katzung, Masters, Trevor.
Basic and clinical
Drug choice

21. • High dose olanzapine, 30-45 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
Drug choice

22. • 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
Drug choice

23. 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
Drug choice

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

25. Katzung, Masters, Trevor.
Basic and clinical
Drug Minimum effective
therapeutic dose
Usual range of
daily doses
Chlorpromazine 100 mg 100-1000 mg
Thioridazine 100 mg 100-800 mg
Perphenazine 10 mg 8-64 mg
Trifluoperazine 5 mg 5-60 mg
Fluphenazine 2 mg 2-60 mg
Thiothixene 2 mg 2-120 mg
Haloperidol 2 mg 2-60 mg
Loxapine 10 mg 20-160 mg
Molindone 10 mg 20-200 mg
Clozapine 50 mg 300-600 mg
Olanzapine 5 mg 10-30 mg
Quetiapine 150 mg 150-800 mg
Risperidone 4 mg 4-16 mg
Ziprasidone 40 mg 80-160 mg
Aripiprazole 10 mg 10-30 mg

26. 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
Dosage

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

28. • 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
Parenteral preparations

29. 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
Parenteral preparations

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

31. • 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
Dosage schedules

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

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

34. • 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
Maintenance treatment

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

36. • 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
Drug combinations

37. • 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
Drug combinations

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

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