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Module 3
Indications
Antipsychotics for Schizophrenia
Flavio Guzmán, MD
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
Psychosis & Schizophrenia
Antipsychotics are not
specific for
schizophrenia
(“antischizophrenic”)
Psychotic
symptoms
• Schizophrenia
• Schizoaffective
disorder
• Mood disorders
• Dementia
• Personality disorders
• Medical conditions
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of
Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.
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.
The “Ideal” treatment for schizophrenia
Positive
symptoms
Negative
symptoms
Based on:
Cognitive
deficits
Gründer G, Hippius H, Carlsson A. The “atypicality”
of antipsychotics: a concept re-examined and redefined. Nature Rev Drug Disc 8:197-202, 2009
FGAs improve positive symptoms
Effectiveness
Positive
symptoms
Antipsychotics
Negative
symptoms
Based on:
Cognitive
deficits
Gründer G, Hippius H, Carlsson A. The “atypicality”
of antipsychotics: a concept re-examined and redefined. Nature Rev Drug Disc 8:197-202, 2009
SGAs: effective for positive symptoms, less EPS
Effectiveness
Variable
efficacy
Positive
symptoms
SGAs
Negative
symptoms
Based on:
Cognitive
deficits
Gründer G, Hippius H, Carlsson A. The “atypicality”
of antipsychotics: a concept re-examined and redefined. Nature Rev Drug Disc 8:197-202, 2009
-Some studies suggest that
SGAs are superior to FGAs
in improving cognition.
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
- 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
Not effective
Effective
SGAs and cognition: the debate
Janicak, P G., S R. Marder, and M N. Pavuluri. Principles
and Practice of Psychopharmacotherapy. 5th ed.
Philadelphia: Lippincott Williams & Wilkins, 2010.
Secondary Negative Symptoms
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.
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.
Treatment phases
•First Episode
Acute phase
•Psychotic Relapse
Maintenance
phase
Assessment
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 http://www.uptodate.com/
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 http://www.uptodate.com/
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 http://www.uptodate.com/
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 http://www.uptodate.com/
Acute Phase Management
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
Short-acting parenteral preparations
Advantages
Disadvantages
• Useful in acute
• Risk of injury to the
agitation
patient and the
caregiver
• Bypass first-pass
metabolism in the liver • High doses of highand gut
potency drugs can lead
to dystonia or akathisia
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed.
John Wiley & Sons, 2008
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;60:1228-35
Antipsychotic choice
Previous response
Adverse effects profile
• EPS: high potency FGAs (haloperidol)
• Weight gain and metabolic effects: olanzapine,
clozapine
• Hyperprolactinemia: FGAs, risperidone, paliperidone
Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of
Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.
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.
Refractory Symptoms
• Assessment
• Management
Assessing refractory symptoms in
schizophrenia
Check adherence to treatment
Check adequacy of time and dose
Review diagnosis
Consider other causes of non-response
• Comorbid substance misuse
• Physical illness
National Institute for Health and Clinical Excellence (2011) [Schizophrenia].
[CG82].
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 http://www.uptodate.com/
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 http://www.uptodate.com/
Switching antipsychotics
Standard cross-titration
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance
phase treatment. UpToDate. Retrieved from http://www.uptodate.com/
Medication changes
Higher relapse risk
Stroup, S., Marder S. (2012). Pharmacotherapy for schizophrenia: Acute and maintenance
phase treatment. UpToDate. Retrieved from http://www.uptodate.com/
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 http://www.uptodate.com/
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 http://www.uptodate.com/
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.
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
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 http://www.uptodate.com/
Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008