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Long-term Safety consideration of Psychosis Treatment

Long-term Safety consideration of Psychosis Treatment. Continuum of Care for schizophrenia. Efficacy. Improving Mood and Negative Symptoms. Improving Cognition. Controlling Positive Symptoms. Improving Quality of Life. Relationships, social roles Community involvement

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Long-term Safety consideration of Psychosis Treatment

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  1. Long-term Safety consideration of Psychosis Treatment

  2. Continuum of Care for schizophrenia Efficacy Improving Mood and Negative Symptoms Improving Cognition Controlling Positive Symptoms Improving Quality of Life • Relationships, social roles • Community involvement • Independent living • Depression, suicide • Social withdrawal • Lack of motivation and interest • Attention, judgment, memory • Agitation • Hostility • Aggression • Hallucinations • Delusions • Paranoia Prevention of Relapse Acute Phase Stabilisation Phase Stable Phase • EPS • Acute dystonia • Sedation • Orthostasis • QTc prolongation • EPS • Drug-drug interactions • QTc prolongation • TD • EPS • Hyperprolactinaemia • Weight gain • Hyperglycaemia • Metabolic syndrome • Cardiac safety Safetyand Tolerability

  3. Tardivedyskinesia • EPS: most powerful predictor, at least a twofoldgreater risk of developing TD (Keepers GA 1991; Kane JM,1988; Chouinard G 1988) • 2004 report: Annual Incidence of TD in adult:5%: conventional antipsycotic(Waddington JL 1993)0.8%: Atypical antipsychotics(Correll C et al, AJP 2004) • 2008 report: 5.5% for Conventional antipsychotics 3.9% for Atypical antipsychotics (Correll C et al, Curr.Opin.Psychiatry 2008.Mar)

  4. Incidence of TD with atypical versus conventional antipsychotics, a prospective cohort study. Woods SW. Journal of Clinical Psychiatry 2010.Jan

  5. Correlation of decreased FA value and clinical ratings( Bai, 2009)

  6. Hyperprolactinaemia and antipsychotics Effects on prolactin Haloperidol and chlorpromazine increase prolactin levels compared with quetiapine Modest persistent prolactin elevation Placebo-level plasma prolactin Dose-related sustained prolactin elevation Conventional antipsychotics Olanzapine Quetiapine Risperidone Sexual dysfunction, Ammenorrhea, gynaecomastia, osteoporosis Wieck & Haddad 2003; Copolov et al 2000; Emsley et al 2000;Olanzapine Prescribing Information 2005; Arvanitis et al 1997; Kleinberg et al 1999

  7. Prolactin level: 24-month ranomized control trial (Bai, unpublished data) Between groupp<0.0001

  8. Bone Density-24-month randomized comparative study (Bai, unpublished data) Between group P<0.05

  9. Atypical antipsychotics and pituitary tumors: FDA pharmacovigilance study. Szarfman A, Pharmacotherapy. 2006

  10. Weight gain with antipsychoticsmeta-analysis (10-week) • Allison DB et al: Am J Psychiatry 1999; 156(11): 1686-96: 81 studies

  11. long-term weight change in Taiwan hospitalized patients(N=876, Bai) Olanzapine,N=188 Clozapine,N=349 Conventional antipsychoticN=342

  12. Weight gain associated with clozapinepersisted for 42-46 months in Taiwan and Caucasian patients 82 clozapine outpatient weight gain till 46 months (Henderson, AJ P 2000) Ya Mei Bai et al, Schizophrenia Research 2009, 108(1-3):122-6

  13. Weight gain with clozapine: 8-year cohort naturalistic study amonghospitalized Chinese schizophrenia patients ( Bai YM, Schizophrenia research 2009, 108: 122-126

  14. Weight gain with clozapine: 8-year cohort naturalistic study amonghospitalized Chinese schizophrenia patients ( Bai YM, Schizophrenia research 2009, 108: 122-126

  15. Association of Initial Antipsychotic Responseto Clozapine and Long-Term Weight Gain BaiYM, American Journal Psychiatry, 2006

  16. Age at Initiation of antipsychotic and 12-month weight gain (N=722) P=0.0023 between group repeated measurement

  17. Baseline BMI and 12-month weight gain (N=722) P<0.001

  18. Predictors for weight gain(6-week study for olanzapine and risperidone) Basson BR, n=268, JCP 2001

  19. Pharmacogenetic studies for clozapine-associated weight gain in Asia Negative study (4-month ) • adrenergic beta3 receptor (Trp64Arg) and G-protein beta3 subunit gene (C825T) . N=87 . Tsai SJ 2004 • 5HT(2C) 759C/T genetic variation of. N=80. Tsai SJ 2002 • TNF-alpha gene -308G/A polymorphism.N=99. Tsai SJ.2003 • Histamine-1 receptor (glu349asp).N=88 : Hong CJ,2002 • serotonin 2A, serotonin 2C and serotonin 6 .N=93 : Hong CJ,2001 Positive study (1-6.7years) • Leptin G2548A polymorphism for male patients. N=102 (Zhang XY, 2007) • G protein beta3 subunit C825T polymorphism . N=134 (Wang YC, Bai YM,2005 ) • adrenergic receptor alpha 2a -1291C>G.N=134 (Wang YC, Bai YM,2005) Positive study in 6-week first episode • serotonin 5-HT(2C) -759T.32 cases Reynolds GP,Am J Psychiatry. 2003

  20. Pharmacogenetic studies for clozapine-associated weight gain in Western countries Negative study: 2 weeks to 14-week5-HT2C Cys23Ser, N=152.(Rietschel M, 1997) 5-HT2C Cys23Ser, -759C/T, and (GT)12-18/(CT) 4-5) N=139 (De Luca V,2007) TNF- G-308A,N=149 . 6-week weight change. (Zai G,2006) Positive study : 6 months HTR2C haplotype A (-759C, -697G, and 23Cys) in 18 clozapine patients (Gunes A, J Clin Psychopharmacol. 2009)

  21. Prevalence of MS among psychiatric patients

  22. Cohort Predictive model for developing MetS(N=510, Bai,Schizo Res2009 ) *p<0.05, **P<0.01, ***p<0.001

  23. Glucose dysregulation independent of adiposity in clozapine • Non-obese patients with clozapine had significant insulin resistance and impairment of glucose effectiveness by IVG test ( Henderson 2005,2006) • No significant associations between the prevalence of diabetes and BMI or body fat among 101 patient treated with clozapine(Lamberti, 2005) • Diabetogenetic effect: direct effect on glucose regulation by limiting the capacity of β-cells to secrete appropriate amount of insulin (Koller E 2001; Scheen AJ, 2007)

  24. Acute Effect of single dose clozapine:decreased insulin secretion and peripheral glucose utilization.(Chintoh AF, 2009)

  25. Increased risk of DM with treatment duration by cohort analysis ( Bai YM, Journal of Clinical Psychiatry, accepted)

  26. Increased risk of DM with treatment duration by cross-sectional analysis ( Bai YM, Journal of Clinical Psychiatry, accepted)

  27. Bipolar disorder and cardiomatabolic disease • Biological:Hypothalamic-pituitary-adrenal (HPA), the immune and autonomic nervous systems • Life style: diet exercise and comorbid substance use( smoking, alcohol, illegal drug) • Medication:Antipsychotic + mood stabilizers ( depakene, lithium)+ antidepressant(?)

  28. 12-month Weight gain of atypical antipsychotics Caucasian report • Clozapine:↑ 5.3-6.3 Kg • Olanzapine: ↑6.8-11.8 Kg • Quetiapie : ↑ 2.7-5.6 Kg • Risperidone: ↑ 2.0-2.3 Kg ( Bustillo AJP 1996, Nemeroff CB JCP 1997) Asia report • 96 cases (46 female, 50 male): ↑6.93 Kg/14 m (Bai YM: Psychiatric Services 1999)

  29. Weight changein bipolar disorder(Kim B, Journal of affective disorder 2008)

  30. DM and Schizophrenia, bipolar disorder健保資料庫100萬人cohort

  31. Hyperlipidemia and Schizophrenia, bipolar disorder 健保資料庫100萬人cohort

  32. Relative Risk of DM in Schizophrenia and Bipolar disorder compared to General Population by age( Taiwan NHI 2000-2007)

  33. Relative Risk of hyperlipidemia in Schizophrenia and Bipolar disorder compared to General population by age ( Taiwan NHI 2000-2007)

  34. Higher BMI with poorer bipolar outcome (Calkin, bipolar disorder 2009)

  35. Higher BMI with poorer bipolar outcome (Calkin, bipolar disorder 2009)

  36. Management of overweight/Metabolic syndrome 1.Monitor : body weight, anthropometric and metabolic assessment2. Behavioral modification( diet/exercise) 3. Switch to other antipsychotic 4. Pharmacological treatment

  37. Protocol for monitoring 2nd-generation antipsychotic therapy(2004) (Adapted from Diabetes Care 27, 2004)

  38. Changes in monitoring practice after FDA warning and ADA/APA consensus (Haupt DW. AM J Psychiatry 2009.Mar)

  39. Under-recognized metabolic syndrome in clinical practice in Taiwan

  40. Low diurnal variability of adiponectin Plasma adiponectin levels have relatively low biovariability and that adiponectin can be sampled fasting or non-fasting to provide a reliable marker of insulin resistance and incipient type 2 diabetes. SHAND B: Clin Chem Lab Med. 2006;44(10):1264-8

  41. Adiponectin as a potential biomarker for the metabolic syndrome (Bai, Journal of Clinical Psychiatry, 2007;Schizophrenia Research 2009)

  42. Easy and Low-Cost Identification of Metabolic Syndrome in PatientsTreated with Second-Generation Antipsychotics: Artificial Neural Networkand Logistic Regression Models (Lin CC, Bai YM, Journal of Clinical Psychiatry. 2010; 71(3):225-234) Artificial Neural Network

  43. Identification of Metabolic SyndromeInternal and external validation( Lin, Bai, Journal of Clinical Psychiatry 2010; 71(3):225-234)

  44. Easy and Low-Cost Identification of Metabolic Syndrome in PatientsTreated with Second-Generation Antipsychotics: Artificial Neural Networkand Logistic Regression Models (Lin CC, Bai YM, Journal of Clinical Psychiatry, 2010; 71(3):225-234) Risk score = 0.193 x WC (cm) + 0.109 x DBP (mm Hg)+ 1.47 xfemale (cut-point for MetS was 25.7)

  45. Management of overweight/Metabolic syndrome 1.Monitor : body weight, anthropometric and metabolic assessment2. Behavioral modification( diet/exercise) 3. Switch to other antipsychotic 4. Pharmacological treatment

  46. Dietary control and physical activity for overweight patients on clozapine: 24-week randomized control studyWu MK, Wang CK, Bai YM: Psychiatric services 2007 • Sample: 53 schizophrenia patients on clozapine with BMI > 27 • Intervention: • Diet calory:1300-1500/day for women, 1600-1800/day for menReduced calorie intake by 200-300 kcal/day Exercise: level walking and walking on stairs for 30mins, three days a week

  47. Dietary control and physical activity for overweight patients on clozapine: 24-week randomized control studyWu MK, Wang CK, Bai YM: Psychiatric services,2007 Hip C Body weight BMI Waist C

  48. Dietary control and physical activity for overweight patients with clozapine- 48 week RCT trial

  49. Management of overweight/Metabolic syndrome 1.Monitor : body weight, anthropometric and metabolic assessment2. Behavioral measurement( diet/exercise) 3. Switch to other antipsychotic 4. Pharmacological treatment

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