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”) 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 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 Cognitive deficits Gründer G, Hippius H, Carlsson A. The “atypicality” of antipsychotics: a concept re-examined and re-defined. Nature Rev Drug Disc 8:197-202, 2009 Based on:

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 8:197-202, 2009 Based on:

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 8:197-202, 2009 Based on:

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.

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.

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 Psychotic Relapse Acute phase 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 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

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;60:1228-35

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.

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 Comorbid substance misuse Physical illness Consider other causes of non-response 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