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Effectiveness of Aripiprazole in Patients with Schizophrenia A Focus on Acute Treatment

Effectiveness of Aripiprazole in Patients with Schizophrenia A Focus on Acute Treatment. 金哲應 ( 仁荷大學病院 ). Schizophrenia( 調鉉病 ) ?. Genetic predisposition likely establishes a psychosis “threshold”; subject to environmental factors

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Effectiveness of Aripiprazole in Patients with Schizophrenia A Focus on Acute Treatment

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  1. Effectiveness of Aripiprazole in Patients with SchizophreniaA Focus on Acute Treatment 金哲應(仁荷大學病院)

  2. Schizophrenia(調鉉病) ? • Genetic predisposition likely establishes a psychosis “threshold”; subject to environmental factors • Etiology unknown; abnormal neuronal circuitry e.g., cortico-limbic-thalamic, is suspected • Implicates multiple CNS neurotransmitters • Incidence of 1% worldwide • Early age of onset (15-25 years) and a chronic, relapsing course are common

  3. Schizophrenia(調鉉病) • Lifelong disabling psychiatric disorder • Severe & variable symptoms : positive, negative symptoms, cognitive deficits, depressive symptoms. • At present, NO CURE ,but Manageable

  4. Vital Statistics in Schizophrenia • 1% prevalence worldwide • Impaired functioning and disability • Old studies : 20% shorter life expectancy • New studies: 30-40% reduction in potential life-years • Higher suicide risk(10%5.6%(Palmer et al 2005) • Higher all-cause mortality APA2007, Nasrallah HA

  5. Evolution of treatments for schizophrenia

  6. Impact of treatment services on proximal and distal outcomes in schizophrenia

  7. Clozapine Haloperidol Fluphenazine Thioridizine Loxapine Perphenazine ECT Risperidone Olanzapine Quetiapine Typical Antipsychotics Ziprasidone Atypical Antipsychotics Chlorpromazine Aripiprazole The Next-generation Atypical Antipsychotic Developments in Medical Treatments for Psychotic Disorders ‘30s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s ‘00 Reserpine

  8. The 3 Phases of Drug Treatment Phases of treatment Acute • Administered during the period from the beginning of a psychotic episode to a clinical response, ideally remission1 Continuation • Ongoing treatment of the psychotic episode from the point of clinical response to the point of recovery1 Maintenance • Optimize protection against the recurrence of episodes1 • Frequency and number of episodes can be reduced with maintenance therapy2 Continuation = Maintenance 1. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press;2007. 2. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry. 2002;63:5–12.

  9. 1~2 days 1~2 weeks 3 month 6 month 1~2 years Treatment goals of Schizophrenia by Phase Relapse prevention Behavior control Symptom control Sedation Positive symptom control Agitation control - Aggressive behavior - Violent behavior - Hostility Stabilize positive symptom Negative symptom control Affective symptom control Cognitive functioning Physical functioning for recovery Stabilize positive symptom Negative symptom control Affective symptom control Cognitive functioning Physical functioning for recovery Diagnosis Non-specific? Acute EPS -Dystonia -Akathisia EPS TD Weight gain Cardiometabolic disturbance Prolactin elevation Safety & Tolerability Sedation disturb functioning Efficacy

  10. Acute Phase of Treatment • Goals - Develop alliance with the patient and family - Prevent harm - Control disturbed behavior - Reduce the severity of psychosis and associated symptoms(eg, agitation, aggression, negative symptoms, affective symptoms) • Pharmacotherapeutic interventions • Weeks to months

  11. Limitation of Typical & Atypical Antipsychotics (except Abilify) • Mechanism of Action • Dopamine antagonists • Efficacy • Inadequate response of negative and cognitive symptoms • Safety & Tolerability • Pervasive side effects • Weight gain • Diabetes • Dyslipidemias • Anticholinergic side effects • Sedation • Hyperprolactinemia

  12. Efficacy vs Effectiveness • Efficacy : how wella medication worksas established through rigorous & controlled clinical investigation • Effectiveness : usefulnessof a medication under conditions of actual clinical practice • Effectiveness=Efficacy+Tolerability+ • Adherence+Ease of use

  13. Abilify는? • Unique MOA(SDADSS) • Partial Agonist • Sedation • 효능 : Efficacy & Effectiveness • 안전성 : 대사장애, 체중증가, 고프로락틴 유발 위험 없다. • 다양한 적응증

  14. Aripiprazole andDopamine Partial Agonism • Aripiprazole is a high-affinity D2 partial agonist • Functional antagonist under conditions of dopamine hyperactivity in limbic cortex (i.e., helps in control of positive • symptoms) • Functional agonist in conditions of dopamine hypoactivity in prefrontal cortex and basal ganglia (ie, control of negative symptoms, cognitive improvement, minimal motor effects) Dopamine system stabilizer Burris et al. J Pharmacol Exp Ther. 2002;302:381.

  15. Aripiprazole Pharmacology related to Serotonin Rc • Abilify also has a partial agonism effect at 5-HT1A receptors. 5-HT1A receptors is associated with improvements in anxiety, depression, cognitive and negative symptoms, and decreased risk of EPS. 5-HT1A agonism also regulates D2 dopamine. • 5-HT2A antagonismallows these medications to have anti-depressantefficacy as well as reduces reliability for EPS by regulating dopamine itself.

  16. Aripiprazole Activity at Receptors Associated To Its Side Effects • Moderate-low affinity at 1 and H1;no affinity for muscarinic receptor subtypes • Potential clinical impact • Low propensity for orthostatic hypotension(1-adrenergic receptors) • Low liability for weight gain and somnolence(H1 histamine receptors) • Low potential for cognitive impairment (muscarinic cholinergic receptors) Data on file.

  17. US FDA Approval (AbilifyTM) • 2002.11 : Schizophrenia • 2003. 09 : Maintenancetherapy, Sch. • 2004.10 : Acute Bipolar mania, including manic & mixed episode • 2005. 03 : Maintenancetherapy, Bipolar • 2007. 11 : Adolescent schizophrenia ( 13~17 year) • 2007.11 : Add-On Treatment of MDD • Tourette • AbilifyInjection : Agitationass. With schizophrenia or bipolar disorder, manic or mixed • * Bipolar Dep, PTSD(Anxiety), OCD(add on), Anhedonia?

  18. Real world consideration of Acute Management

  19. Issues of Abilify Starting • Acute management • Starting dose • - 10~20mg starting • - for inadequate response : inc dose as quickly as possible • - for sedation : use BZ at a full dose in concomitant therapy • Activation issue associated with dose in acute phase • - generally, activation occurs at a low dose • - to manage activation, inc dose or use BZ

  20. Aripiprazole, Ziprasidone, and Quetiapine in the Treatment of First Episode Nonaffective Psychosis Crespo-Facorro B et al. J ClinPsychopharmacol 2013;33:215-220

  21. Clinical Efficacy • Rate of Responder - Ari : 63.6%, Zip : 42.0%, Quet : 46.2% (p=0.047) • Adverse Events 1) somnolence : Ari 21.2%, Zip : 40.0%, Quet : 45.0%(p=0.020) 2) Akathisia : Ari : 22.7%, Zip 16.0%, Quet : 2.5%(p=0.020)

  22. The efficacy of aripiprazole in the treatment of multiple symptom domains in patients with acute schizophrenia: A pooled analysis of data from the pivotal trials John M. Kane a,⁎, Sheila Assunção-Talbott b, James M. Eudicone b, Andrei Pikalov c, Richard Whitehead c, David T. Crandall b a The Zucker Hillside Hospital, New York, NY, USA b Bristol-Myers Squibb, Plainsboro, NJ, USA Schizophrenia Res. 2008;105:208-215

  23. Changes in PANSS total score & Subscale scores

  24. PANSS Positive Items

  25. PANSS Negative Items

  26. PANSS General Psychopathology Items

  27. Olanzapine versus Aripiprazolefor the treatment of Agitation in Acutely ill patients with Schizophrenia . J ClinPsychopharmacol 2008;28:601-607.

  28. Study Design • 5-day, randomized, double-blind trial • Ho : Owing to its pure antagonist activity, olanzapine would be superior to aripiprazole in reducing agitation and positive symptoms early in the treatment of acutely ill patients.

  29. -2 -4 -6 -8 -10 p=0.851 Visit 2 p=0.103 Visit 3 p=0.531 Visit 4 p=0.671 Visit 5 PANSS-EC Score Change Olanzapine Aripiprazole Between treatment p-value from repeated measures ANOVA model: Change baseline score + treatment + visit + investigator + visit treatment + visit baseline score. Kinon, 2008

  30. OlanzapineAripiprazole 35 20 80 30 10 60 25 0 20 -10 40 15 -20 10 20 -30 5 0 -40 0 Metabolic Parameters p<0.001 p=0.030 p<0.001 Glucose (mg/dL) Prolactin(μg/L) Triglycerides (mg/dL) Kinon, 2008

  31. Akathisia concern with Abilify • About 10~20% of patients(3~5%) • Generally mild to moderate in intensity • Treat as you would with other antipsychotics • Consider dose reduction • Treat with beta blockers • Not generally associated with discontinuation

  32. Evaluation of AkathisiaA Post hoc Analysis of Pooled Data Kane JM et al. J Psychopharmacol 2010;24:1019-1029.

  33. Akathisia • No consensus diagnostic criteria • DSM(APA 1994) : - medication-induced movement disorder that is characterized by motor restlessness accompanied by increased nervous and restless movement • Subtypes : 1) withdrawal 2) acute 3) tardive akathisia • BARS(Barnes Akathisia Rating Scale)

  34. Akathisia, Agitation, Activation, and Aggravation

  35. Summary - Results • Akathisia with Aripiprazole - occurred early in treatment - mild to moderate in severity - led to few study discontinuations - did not compromise therapeutic efficacy

  36. Proposed strategies for successful clinical management with Aripiprazole Mago R. Expert Opinion Pharmacother 2008;9:1279-1290

  37. General Issues related to Dosing • Lack of sedation = lack of efficacy • Agitation  BZ • AE = mild to moderate, transient in nature ; waiting, dosage modification, or adjunctive medication • Long-term benefits outweigh the short term adverse effects

  38. Dosing Strategies(Expert Opinion)

  39. Clinical Factors Rapid/High-dose Slow/Low-dose Patients younger older healthy medical co-morbid motivated for tx ambivalent Illness acute exacerbated stable sx agitated calm Treatment inpatient outpatient tolerating Aps drug naïve, intoler Others good support limited support

  40. Proposed Initiation/Dosing Strategies Rapid/High-dose Slow/Low-dose Starting D 20mg 5mg Target 30mg 10mg Speed immediate 1 week observe safety/se 2nd day increase or decrease Taper period 4-8 weeks(clo, olan 12weeks) begin tapering when target dose reached Worsening inc dose or add on incr dose

  41. Factors Modifying Dosing Strategies • Treatment naïve ; half dose(10mg) • Age : <18 or >65 ; quarter dose(5mg) • Medical morbidity ; half or quarter dose • Concommitant medications - fluoxetine/paroxetine ; half dose - carbamazepine ; twise the dose

  42. Management of adverse events with Aripiprazole • Akathisia ; BZ(clonazepam 0.5~1mg, bid or qid), beta-blocker(30-120mg), reduce dose first & medication • Anxiety/agitation ; BZ(lorazepam 0.5~1mg, qid) • Sedation/somnorance ; wait & changed to bedtime dose reduce the dose • Insomnia ; morning dose with food & add hypnotics • Nausea/vomiting ; food, reduce dose, bed time, dividing dose • EPS ; • Worsening symptoms

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