1. Antipsychotics: The Essentials Module 4 Metabolic & Other Adverse Effects
Flavio Guzmán, MD

2. Outline Metabolic effects Hyperprolactinemia Cardiovascular effects
Anticholinergic effects
Sedation
Agranulocytosis
Other effects

3. Metabolic Side Effects
Weight Gain
Diabetes
Dyslipidemia

4. Weight Gain Why is it important?
Schizophrenia patients are more likely to be overweight or obese than individuals without schizophrenia.
Affects self-image.
Cause of poor treatment adherence.
Serious effects on health and life expectancy (hypertension, CAD, T2DM, stroke).
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

5. Weight Gain: Possible Mechanisms
Changes in appetite and satiety mediated by H1 antagonism.
Antagonism of 5HT2C receptors might also contribute.

6. Weight Gain: Three Levels of Risk
Level of risk
Antipsychotic
High
Clozapine
Olanzapine
Intermediate
Risperidone
Quetiapine
Little or no significant weight gain
Aripiprazole
Ziprasidone
Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):

7. Weight Gain: Monitoring
Frequent monitoring of BMI (kg/m2)
BMI 25-30: Overweight
BMI ˃ 30 : Obese
Waist circumference monitoring
Central obesity is a risk factor for diabetes, hypertension and dyslipidemia
Abdominal obesity:
Men: ˃ 102 cm (˃ 40 in.)
Women: ˃ 88 cm (˃ 35 in.)
Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):

8. Diabetes
The prevalence of T2DM is twice as high among patients with schizophrenia as in the general population.
Clozapine and olanzapine are more often associated with T2DM than are FGAs or other SGAs.
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

9. Diabetes & Antipsychotics: Possible Mechanisms
Weight Gain
Antipsychotics
Diabetes
Insulin resistance
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

10. Diabetes & Antipsychotics: Monitoring
Fasting glucose level or hemoglobin A1c
Before starting a new antipsychotic: baseline levels.
3-4 months after.
At least annually.
Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):

11. Antipsychotics & Dyslipidemia
Increase of :
Total cholesterol
LDL
TG levels
Cholesterol Increase
Antipsychotic
High
Clozapine
Olanzapine
Modest
Risperidone
Quetiapine
Neutral
Aripiprazole
Ziprasidone
Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):

12. Monitoring for Dyslipidemia
Lipid profile at baseline
If LDL level is normal (≤: 130mg/dl): lipid panel once every 2 years
If LDL level is ˃ 130 mg/dl: lipid panel every 6 months
Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):

13. Hyperprolactinemia

14. Tuberoinfundibular Pathway & Prolactin Release
Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland.
Dopamine tonically inhibits prolactin release.
Physiology
D2 antagonism increases prolactin levels.
Implication

15. Tuberoinfundibular Pathway & Prolactin Release
Antipsychotics increase prolactin by blocking D2 receptors in the tuberoinfundibular pathway

16. Hyperprolactinemia: Clinical Features
Galactorrhea
Amenorrhea
Sexual dysfunction
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

17. Antipsychotics & Hyperprolactinemia
Concerns of:
Osteoporosis
Breast cancer
Common:
FGAs
Risperidone and paliperidone
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

18. Cardiovascular Effects
Orthostatic Hypotension
QT prolongation

19. Orthostatic Hypotension

20. Orthostatic Hypotension
Tachycardia
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

21. Orthostatic Hypotension
Alpha 1 blocking effects:
Chlorpromazine, thioridazine
Clozapine, olanzapine, risperidone
Dose-related effect
Can subside due to tolerance
Start low, increase gradually
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

22. Orthostatic Hypotension
More dangerous in the elderly or medically ill patients.
Chief danger: fainting or falling , injuries can produce significant morbidity.
When appropriate:
Check for history of orthostatic hypotension
Warn patients
Monitor BP (lying and standing) after the first dose and during first few days of treatment.
Instruct patients to sit or stand up slowly
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

23. QT prolongation

24. Antipsychotics & QT prolongation
QT prolongation can lead to torsades de pointes (can progress to ventricular fibrillation).
More useful to refer to the corrected QT interval corrected (QTc).
A QTc interval of 500 ms or greater is considered a risk factor for torsades de pointes.
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

25. Antipsychotics & QT prolongation
FGA
Low potency
Thioridazine
Mesoridazine
Chlorpromazine
Pimozide
SGA
Ziprasidone
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

26. Anticholinergic Effects

27. Anticholinergic Effects
CNS
Cognitive dysfunction
Peripheral
Autonomic Effects
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

28. Peripheral Anticholinergic Effects
Dry Mouth
Blurred vision
Constipation
Urinary retention
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

29. Antipsychotics with Anticholinergic Effects
Chlorpromazine
Clozapine
Olanzapine
Quetiapine
Iloperidone
Marder, S (2011). Pharmacotherapy for schizophrenia: Side effect management. In: Murray B Stein(Ed.), UpToDate.

30. Sedation Usually occurs during the first days of treatment.
Some patients rapidly develop tolerance.
Dose related effect.
Can be useful early in treatment.
Cause of poor treatment adherence.
Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

31. Sedation: Receptors Involved
Histamine
Acetylcholine
Norepinephrine
Stahl, S M. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambrigde University Press; 2008

32. Sedation and Antipsychotic Potency
Lower potency, higher sedation
Sedating antipsychotics: clozapine, chlorpromazine and thioridazine.
Risperidone, haloperidol and fluphenazine: more potent and less sedating.
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

33. Clinical Considerations
Rapid discontinuation can lead to rebound insomnia
Slow tapering
Add other sedative medications (antihistamines) or hypnotics (benzodiazepines and non-benzodiazepines).
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

34. Clozapine-Related Agranulocytosis
ANC ˂ 500/mm3
WBC ˂ 2000/mm3
Potentially fatal condition
Requires immediate medical attention

35. Clozapine-Related Agranulocytosis
Before starting clozapine:
WBC ≥ 3,500/ mm3
ANC ≥ 2,000/ mm3
Risk:
Increases with age
Higher in women
Fever or any sign of infection is an immediate indication for WBC.
If WBC ˂ 2000/mm3 or ANC ˂ 1000/mm3 : discontinue clozapine.

36. Monitoring for Clozapine-Related Agranulocytosis
First 6 months: weekly monitoring (*)
6-12 months: every 2 weeks monitoring (*)
After 12 months: monthly monitoring (*)
(*) If WBC ≥ 3,500/ mm3 ANC ≥ 2,000/ mm3

37. Seizure Threshold Antipsychotics tend to lower the seizure threshold.
Usually not contraindicated in patients with seizure disorders but should be used with caution.
Clozapine has a black box warning for this effect.

38. Hepatic Effects Severe hepatic effects are rare.
Asymptomatic elevations of liver enzyme levels occur during the first 3 months of treatment.
% of patients treated with chlorpromazine can develop cholestatic jaundice.
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

39. Skin & Eye Complications
Chlorpromazine can cause:
Pigmentation of skin areas exposed to light and pigment deposits in the eye.
Photosensitivity
Retinal pigmentation occurs only with thioridazine (serious irreversible effect above 800 mg/day).
Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010.

40. References and Further Reading
Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):
Clozapine manufacturer prescribing information:
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
Janicak, P G., Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.
Schatzberg, AF., Cole, JO, and DeBattista, C. Manual of Clinical Psychopharmacology. 7th ed.American Psychiatric Publishing, 2010