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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