1. Adverse effects of antipsychotic drugs
Domina Petric, MD

2. Behavioral effects
The older typical antipsychotic drugs are unpleasant to take.
This can be mitigated by giving small doses during the day and the major portion at bedtime.
Pseudodepression may be due to drug-induced akinesia: usually responds to treatment with antiparkinsonism drugs.

3. Behavioral effects
Other pseudodepressions may be due to higher doses than needed in a partially remitted patient: decreasing the dose may relieve the symptoms.
Toxic-confusional states may occur with very high doses of drugs that have prominent antimuscarinic actions.

4. Neurologic effects
Extrapyramidal reactions occurring early during treatment with older agents include:
typical Parkinson´s syndrome
akathisia (uncontrollable restlessness)
acute dystonic reactions (spastic retrocollis or torticollis)

5. Neurologic effects Levodopa should never be used in these patients!
Parkinsonism can be treated with conventional antiparkinsonism drugs of the antimuscarinic type or with amantadine (rarely).
Levodopa should never be used in these patients!
Parkinsonism may be self-limiting.
An attempt to withdraw antiparkinsonism drugs should be made every 3-4 months.

6. Neurologic effects
Akathisia and dystonic reactions are best treated in many cases with sedative antihistamine with anticholinergic properties parenterally or orally: diphenhydramine.

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8. Neurologic effects Tardive dyskinesia
It is a late-occurring syndrome of abnormal choreoathetoid movements.
It is the most important unwanted effect of antipsychotic drugs.
It is probably caused by a relative cholinergic deficiency secondary to supersensitivity of dopamine receptors in the caudate-putamen.

9. Tardive dyskinesia Early recognition is important!
Tardive dyskinesia is estimated to have occurred in 20-40% of chronically treated patients before the introduction of the newer atypical antipsychotics.
Early recognition is important!
Advanced cases may be difficult to reverse.
Quetiapine and clozapine have the least likelihood of causing tardive dyskinesia.

10. Tardive dyskinesia
Any patient with tardive dyskinesia treated with a typical antipsychotic drug or possibly risperidone or paliperidone should be switched to quetiapine or clozapine.
The course of the disorder is variable and sometimes self-limited.
First step should be to discontinue or reduce the dose of the current antipsychotic agent or switch to quetiapine or clozapine.

11. Tardive dyskinesia
Second step would be to eliminate the drugs with central anticholinergic action, particularly antiparkinsonism drugs and tricyclic antidepressants.
The addition of diazepam in doses of mg/day may add to the improvement by enhancing GABAergic activity.

12. Extrapyramidal syndrome (EPS)
Parkinson´s syndrome
Should not be treated with levodopa!
Tardive dyskinesia
EPS
Akathisia
Most important unwanted effect!
Can occur early during treatment.
Acute dystonic reactions
Can occur early during treatment.

13. Neurologic effects
Seizures
De novo seizures may occur in 2-5% of patients treated with clozapine.
Use of an anticonvulsant is able to control seizures in most cases.
Seizures can also be a complication of chlorpromazine treatment.

14. Autonomic nervous system effects
Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs.
Those patients who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action.

15. Autonomic nervous system effects
Orthostatic hypotension and impaired ejaculation are common complications of therapy with chlorpromazine or mesoridazine.
These patients should be switched to drugs with less marked adrenoreceptor-blocking actions.

16. Metabolic and endocrine effects
Weight gain is very common, especially with clozapine and olanzapine.
This requires monitoring of food intake, especially carbohydrates.
Hyperglycemia may also develop, as well as hyperlipidemia.
The management of weight gain, insulin resistance and increased lipids should include monitoring of weight at each visit and measurement of fasting blood sugar and lipids at 3-6 month intervals.

17. Metabolic and endocrine effects
Measurement of hemoglobin A1C may be useful.
Diabetic ketoacidosis has been reported in a few cases.
The triglyceride:HDL ratio should be less than 3,5 in fasting samples.

18. Metabolic and endocrine effects
Hyperprolactinemia in women results in the amenorrhea-galactorrhea syndrome, which leads to infertility.
HyperPRL in men causes loss of libido, impotence and infertility.
HyperPRL may cause osteoporosis, particularly in women.
Aripiprazole does not raise PRL levels!

19. Toxic/allergic reactions
Agranulocytosis, cholestatic jaundice and skin eruptions…
Clozapine causes agranulocytosis in a small, but significant number of patients: 1-2%.
Agranulocytosis can develop rapidly, usually between the 6th and 18th weeks of therapy.
Patients receiving clozapine must have weekly blood counts for the first 6 months of treatment and every 3 weeks thereafter.

20. Ocular complications
Deposits in the anterior portions of the eye (cornea, lens) are a common complication of chlorpromazine therapy.
These deposits may accentuate the normal process of aging of the lens.

21. Ocular complications
Thioridazine is the only antipsychotic drug that causes retinal deposits.
These deposits may resemble in advanced cases retinitis pigmentosa.
The deposits are usually associated with browning of vision.
The maximum daily dose of thioridazine is limited to 800 mg/day.

22. Cardiac toxicity
Thioridazine in doses exceeding 300 mg daily is almost always associated with minor abnormalities of T waves that are easily reversible.
Overdoses of thioridazine are associated with major ventricular arrhythmias: torsades de pointes, cardiac conduction block and sudden death.

23. Cardiac toxicity
Ziprasidone carries the greatest risk of QT prolongation and should not be combined with other drugs that prolong the QT interval: thioridazine, pimozide, antiarrhythmic drugs 1A and 3.
Clozapine is sometimes associated with myocarditis and must be discontinued if myocarditis manifests.

24. Pregnancy
If a pregnant woman could manage to be free of antipsychotic drugs during pregnancy, this would be desirable because of their effects on the neurotransmitters involved in neurodevelopment.

25. Neuroleptic malignant syndrome (NMS)
This life-threatening disorder occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotic agents.
The initial symptom is marked muscle rigidity.
If sweating is impaired, fever may ensue, reaching dangerous levels: often with anticholinergic drugs.

26. Neuroleptic malignant syndrome (NMS)
The stress leukocytosis may erroneously suggest an infectious process.
Autonomic instability, with altered blood pressure and pulse rate, is often present.
Muscle-type creatine kinase levels are usually elevated, reflecting muscle damage.
Pathophysiology: excessively rapid blockade of postsynaptic dopamine receptors.

27. Treatment Muscle relaxants: diazepam, dantrolene…
Dopamine agonists, such as bromocriptine
Cooling measures
Switching to an atypical drug after recovery!

28. Drug interactions
II.

29. Drug interactions
Antipsychotics produce more important pharmacodynamic than pharmacokinetic interactions!
Additive effects may occur when these drugs are combined with others that have sedative effects, α-adrenoreceptor blocking action and anticholinergic effects.
In the case of thioridazine and ziprasidone it is important not to combine these drugs with those that have quinidine-like action.

30. Overdose
III.

31. Overdose
Poisonings with antipsychotic agents are rarely fatal, except with MESORIDAZINE and THIORIDAZINE.
Drowsiness proceeds to coma with an intervening period of agitation.
Neuromuscular excitability may be increased and proceed to convulsions.
Pupils are miotic.
Deep tendon reflexes are decreased.

32. Overdose ABCD treatment for poisonings and supportive care!
Hypotension and hypothermia are the rule, although fever may be present later in the course.
The lethal effects of mesoridazine and thioridazine are related to induction of ventricular tachyarrhythmias.
ABCD treatment for poisonings and supportive care!

33. Overdose ABCD! MIOSIS CONVULSIONS Drowsiness Other agents rarely
COMA with an intervening period of AGITATION
Other agents rarely
Ventricular tachyarrhythmias
Hypotension, hypothermia
Mesoridazine, thioridazine
FEVER later in the course
Neuromuscular excitability
CONVULSIONS
ABCD!
MIOSIS
Decreased deep tendon reflexes

34. Psychosocial treatment and cognitive remediation
are very important part of the therapy.

35. Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.
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