Module 3 Indications Antipsychotics for Schizophrenia

Flavio Guzmn, 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)
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.

Schizophrenia has multiple psychopathological dimensions

Positive symptoms Negative symptoms Cognitive deficits Mood symptoms Other

Delusions Hallucinations Thought disorder

Apathy Social withdrawal Restricted affect Anhedonia

Attention Memory Executive function

Dysphoria Depression

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

Grnder 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

Antipsychotics

Positive symptoms

Negative symptoms
Based on:

Cognitive deficits

Grnder 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

SGAs
Negative symptoms
Based on:

Positive symptoms

Cognitive deficits

Grnder G, Hippius H, Carlsson A. The atypicality of antipsychotics: a concept re-examined and redefined. Nature Rev Drug Disc 8:197-202, 2009

SGAs and cognition: the debate

Effective
-Some studies suggest that SGAs are superior to FGAs in improving cognition. - 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

Bilder RM, et al: Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 159:10181028, 2002

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
Depression

Secondary
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, 1184

References
American Psychiatric Association ( 2004 ) Practice guideline for the treatment of patients with schizophrenia, 2nd edition . American Psychiatric Publishing, Inc , Washington DC, USA, 1184 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