1. Module 3 Indications Antipsychotics for Schizophrenia
Flavio Guzmán, MD

2. Outline
Clinical aspects of schizophrenia relevant to pharmacological treatment
Acute phase
Pre treatment assessment
Antipsychotic choice
Refractory symptoms: assessment and management
Goals for maintenance phase

3. Psychosis & Schizophrenia
Antipsychotics are not specific for schizophrenia (“antischizophrenic”)
Schizophrenia
Schizoaffective disorder
Mood disorders
Dementia
Personality disorders
Medical conditions
Psychotic symptoms
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

4. Schizophrenia has multiple psychopathological dimensions
Positive symptoms
Delusions
Hallucinations
Thought disorder
Negative symptoms
Apathy
Social withdrawal
Restricted affect
Anhedonia
Cognitive deficits
Attention
Memory
Executive function
Mood symptoms
Dysphoria
Depression
Other
Agitation/ excitement
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

5. The “Ideal” treatment for schizophrenia
Positive symptoms
Negative symptoms
Cognitive deficits
Gründer G, Hippius H, Carlsson A. The “atypicality” of antipsychotics: a concept re-examined and re-defined. Nature Rev Drug Disc 8: , 2009
Based on:

6. FGAs improve positive symptoms
Antipsychotics
Effectiveness
Positive symptoms
Negative symptoms
Cognitive deficits
Gründer G, Hippius H, Carlsson A. The “atypicality” of antipsychotics: a concept re-examined and re-defined. Nature Rev Drug Disc 8: , 2009
Based on:

7. SGAs: effective for positive symptoms, less EPS
Effectiveness
Variable efficacy
Positive symptoms
Negative symptoms
Cognitive deficits
Gründer G, Hippius H, Carlsson A. The “atypicality” of antipsychotics: a concept re-examined and re-defined. Nature Rev Drug Disc 8: , 2009
Based on:

8. SGAs and cognition: the debate
Effective
-Some studies suggest that SGAs are superior to FGAs in improving cognition.
Not effective
- Effects are relatively weak compared to the severity of the impairments
- CATIE trial (NIMH) showed no evidence of benefit of SGAs over FGAs in the treatment of cognitive symptoms
Bilder RM, et al: Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159:1018–1028, 2002
Janicak, P G., S R. Marder, and M N. Pavuluri. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

9. Secondary Negative Symptoms
Primary
Secondary
Depression
Extrapyramidal side effects
Dose reduction
Switch antipsychotic
Anticholinergic drugs
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.

10. Key Points
Antipsychotics (both FGAs and SGAs) are effective for positive symptoms of schizophrenia.
Antipsychotics are used in the management of acute episodes and in the prevention of relapses.
There is a need for more effective treatments for negative and cognitive symptoms.

11. Treatment phases First Episode Psychotic Relapse Acute phase
Maintenance phase

12. Assessment

13. Assessment – Physical exam
Body mass index (BMI)
Waist circumference
Heart rate
Blood pressure
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

14. Assessment – Neurological exam
Signs of a movement disorder:
Extrapyramidal symptoms (EPS): akathisia, parkinsonism, dystonias
Tardive dyskinesia
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

15. Assessment – Lab testing
CBC
Electrolytes
Fasting glucose
Lipid profile,
Liver, renal and thyroid function tests
White blood cell (WBC) count with differential for patients treated with clozapine
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

16. Assessment - ECG History of cardiac disease Antipsychotics: Clozapine
Thioridazine
Iloperidone
Ziprasidone
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

17. Acute Phase Management

18. Management of the acute episode
Tablets
Patients might not swallow the tablet
Hepatic disease or slow GI absorption may increase the time required to attain steady-state concentrations
Liquid concentrates
Orally-dissolving formulations
Short acting parenteral preparations
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

19. Short-acting parenteral preparations
Advantages
Useful in acute agitation
Bypass first-pass metabolism in the liver and gut
Disadvantages
Risk of injury to the patient and the caregiver
High doses of high-potency drugs can lead to dystonia or akathisia
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008

20. Clinical Improvement of Psychotic Symptoms
Treatment Course
Clinical Improvement of Psychotic Symptoms
2 weeks
4 weeks
Months
Based on:
Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Archives of general psychiatry 2003;60:

21. Antipsychotic choice Previous response
EPS: high potency FGAs (haloperidol)
Weight gain and metabolic effects: olanzapine, clozapine
Hyperprolactinemia: FGAs, risperidone, paliperidone
Adverse effects profile
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

22. Key Points
A pretreatment assessment is recommended, although in some situations it may be difficult to implement.
Patients show most of the clinical response in the first 4 to 6 weeks of treatment.
Antipsychotic choice is often guided by previous response to treatment and adverse effects profile.

23. Refractory Symptoms
Assessment
Management

24. Assessing refractory symptoms in schizophrenia
Check adherence to treatment
Check adequacy of time and dose
Review diagnosis
Comorbid substance misuse
Physical illness
Consider other causes of non-response
National Institute for Health and Clinical Excellence (2011) [Schizophrenia]. [CG82].

25. Management of Refractory Symptoms
Dose increase
Switch AP
Add a second AP
Switch to clozapine
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

26. Changing to another antipsychotic
Because of:
Lack of effectiveness
Adverse effects
Can be helpful when a poor response is related to side effects.
Less beneficial when the initial medication lacked effectiveness.
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

27. Switching antipsychotics
Standard cross-titration
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

28. Medication changes Higher relapse risk
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

29. Adding a second antipsychotic
Common practice.
Little evidence supporting the use of two antipsychotics.
Some randomized trials indicated that augmentation of clozapine with another antipsychotic may have some benefit.
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

30. Changing to clozapine
For patients who experience persistent and clinically significant positive symptoms of schizophrenia after trials of two other antipsychotic medications.
Clozapine reduced suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide.
Can cause severe a life threatening side effect: agranulocytosis.
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from

31. Key Points
When assessing refractory symptoms check adherence to treatment, review diagnosis and consider other causes of non-response.
There is little evidence for combining two antipsychotics.
Clozapine can be used after two trials with other antipsychotics.

32. Maintenance Phase Preserve symptom remission Prevent psychotic relapse
Implement a plan for rehabilitation
Optimize functioning
Improve quality of life
American Psychiatric Association ( 2004 ) Practice guideline for the treatment of patients with schizophrenia, 2nd edition . American Psychiatric Publishing, Inc , Washington DC, USA, 1–184

33. References
American Psychiatric Association ( 2004 ) Practice guideline for the treatment of patients with schizophrenia, 2nd edition . American Psychiatric Publishing, Inc , Washington DC, USA, 1–184
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.
National Institute for Health and Clinical Excellence (2011) [Schizophrenia]. [CG82].
Sadock, B J., V A. Sadock, and P Ruiz. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009.
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment. UpToDate. Retrieved from
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008