Understanding Schizophrenia: Clinical Nature, Treatment, and Prognosis

1. 思覺失調症 精神科主治醫師 游佩琳

2. 我國衛生福利部已於2014年5月21日正式發文全國醫療機構把舊的「精神分裂症」病名改譯為中文之「思覺失調症」我國衛生福利部已於2014年5月21日正式發文全國醫療機構把舊的「精神分裂症」病名改譯為中文之「思覺失調症」

3. What is schizophrenia?

4. Schizophrenia: Clinical Nature of the Disorder • A chronic, lifelong disorder with onset in adolescence or early adulthood • Illness is marked by periodic exacerbations and generally incomplete remissions • Even during remissions, residual clinical symptoms and significant impairments in social skills and function are present to varying degrees

5. 思覺失調症的病程會一再復發

6. 大腦灰質隨病程進展而逐漸流失 Earliest deficit p value 0.00002 5 years later (same subjects) 0.0001 0.0005 0.001 0.005 0.01 0.05 SUS-15070516 STG, superior temporal gyrus; DLPFC, dorsolateral prefrontal cortex Thompson et. Al; PNAS of the USA,98(20): 11650-11655, 2001.

7. 0.05 0 -0.05 Excessive decrease in superior frontal grey matter density in patients -0.1 -0.15 -0.2 0 1 2 3 4 5 6 7 8 Number of hospitalizations during scan-interval 復發確實讓腦部再度遭受傷害 Grey matter density decreased with number of hospitalizations in patients with schizophrenia n=92; p=0.03 SUS-15070516 Van Haren et al. Neuropsychopharmacology 2007;32:2057–2066

8. Haloperidol Amisulpride Olanzapine Quetiapine Ziprasidone EUFESTStudy:33% to 72% FEP 於一年內中斷藥物治療 EUFEST: Time to treatmentdiscontinuation FEP:First Episode Patient EUFEST: European First Episode Schizophrenia Trial MKT-INV SUS-TW-0018 Kahn et al. Lancet 2008; 371: 1085–97

9. 症狀與診斷

10. DSM-5 • A. 以下五項須至少出現兩項, 持續至少一個月 1. Delusions 2. Hallucinations 3. Disorganized speech 4. Grossly disorganized or catatonic behavior 5. Negative symptoms • B. 功能下降

11. C. 發病至今至少六個月 • D. 排除情感性疾患 • E. 排除生理疾病或物質濫用 • F. 如果患者為autism spectrum disorder, 必需在明顯妄想或幻覺的狀況下才給診斷

12. Relevant Psychopathological Dimensions of Schizophrenic Illness • Positive symptoms (delusions, hallucinations, thought disorder, etc.) • Negative symptoms (amotivation, avolition, anhedonia, alogia, affective flattening, etc.) • Cognitive impairments (deficits in memory + other intellectual functions)

13. Role of genes and environment • Genetic factors: first-degree relatives---10 times of lifetime risk; Monozygotic twins 50% vs dizygotic twins 10-14% • Linkage study: 6p22-24, 8p22-p21, 22q12-q13.1, 5q, 6q, 9p, 18p, 22q

14. Epidemiology • Lifetime Prevalence: 1% • Male:Female=1:1 • Onset: Male (peak at 17-27) vs female (peak at 17-37) • Suicide: risk of committed suicide 10%

15. 相關的Neurochemistry • Dopamine--- • D2 receptor blockade and antipsychotic medications • Dopamine agonist such as amphetamine • Glutamate--- Glutamate antagonist such as PCP induce psychosis, NMDA receptors • Serotonin---5HT2-binding and the ratio of 5HT2/D2 binding

16. 藥物治療

17. 急性病房

18. 自願住院 vs 強制住院 • 嚴重病人, 係指病人呈現出與現實脫節之怪異思想及奇特行為, 致不能處理自己事務, 經專科醫師診斷認定者. • 嚴重病人傷害他人或自己或有傷害之虞，經專科醫師診斷有全日住院治療之必要者，其保護人應協助嚴重病人，前往精神醫療機構辦理住院。 • 前項嚴重病人拒絕接受全日住院治療者，….指定精神醫療機構予以緊急安置，並交由二位以上專科醫師進行強制鑑定。

19. 前項強制鑑定結果，仍有全日住院治療必要，經詢問嚴重病人意見，仍拒絕接受或無法表達時，應即填具強制住院基本資料表及通報表，並檢附嚴重病人及其保護人之意見及相關診斷證明文件，向衛服部強制住院審查會申請許可強制住院；強制住院可否之決定，應送達嚴重病人及其保護人。前項強制鑑定結果，仍有全日住院治療必要，經詢問嚴重病人意見，仍拒絕接受或無法表達時，應即填具強制住院基本資料表及通報表，並檢附嚴重病人及其保護人之意見及相關診斷證明文件，向衛服部強制住院審查會申請許可強制住院；強制住院可否之決定，應送達嚴重病人及其保護人。

20. 慢性病房 日間留院 • 仍有殘餘症狀但相對穩定 • 具復健潛力 • 家庭支持系統足夠 (視情形而定, 有的慢性病房要外宿, 有的一住經年) • 除服藥控制症狀, 可接受工作訓練 • 病患可自行交通往返 • 白天缺乏活動安排 • 藥物順從性待加強 • 病患不需離開家庭 • 住院時間可長達數年

21. Antipsychotics抗精神病藥物 • 傳統型(第一代) • 1952, Chlopromazine (Wintermin) • High potency vs Low potency • 第二代 • Mixed receptor antagonists • Specific D2/D3 antagonist (Amisulpride) • Partial dopamine agonist (Abilify)

22. Side effects • 多巴胺阻斷引起---EPS (錐體外徑症狀), Tardive dyskinesia (遲發性運動不能), 泌乳激素上升 • 抗膽鹼阻斷作用引起---口乾視力模糊, 解尿困難 • 抗組織胺作用引起---嗜睡, 體重增加 • 抗腎上腺素作用引起---姿勢性低血壓, 頭暈

23. Zooming in on the Dopamine D2 ReceptorDifferences Between Antipsychotics • Degree of binding at dopamine D2 receptors • Different antipsychotics differ in the extent to which they block the dopamine D2 receptor at clinically relevant doses (reflected in % occupancy at the receptor) • Dose-dependent • >60% occupancy believed to be necessary for antipsychotic effect • >70% occupancy believed to be associated with elevated prolactin • >80% occupancy believed to be associated with EPS

24. Options for Antipsychotic Therapies Prior to Antipsychotics Conventional or Atypical Antipsychotics (First Generation) Atypical Antipsychotics (Second Generation) Future Agents 1952 1960s 1980s 1990s 2002 ECT Insulin coma Haloperidol Fluphenazine Thioridazine Loxapine Perphenazine Risperidone Olanzapine Quetiapine Ziprasidone Clozapine Zotepine Amisulpride Aripiprazole Chlorpromazine ECT=electroconvulsive therapy.

25. Receptors Established Benefits Likely Side Effects 5-HT2A receptor Reduced EPS ?? 5-HT2C receptor Not definitely known Weight gain Histamine H1 Not definitely known Sedation, weight gain receptor Muscarinic receptor Not definitely known Blurred vision, dry mouth, constipation, urinary retention, sinus tachycardia, memory dysfunction 1-adrenergic Not definitely known Postural hypotension, receptor dizziness Clinical Implications of Blockade of Various Receptors by Antipsychotics

26. Ziprasidone Haloperidol Risperidone 5-HT2A D4 5-HT2A 5-HT2A D2 D2 a1 a2 5-HT2C D1 5-HT1A 5-HT1D D2 a1 H1 H1 a1 5-HT2C Clozapine Quetiapine Olanzapine 5-HT2A M1 H1 M1 5-HT2A M1 D2 D2 D2 5-HT2A 5-HT1A a1 5-HT1A 5-HT2C 5-HT2C 5-HT2C a1 H1 H1 a1 Comparative Pharmacology of Atypical Antipsychotic Drugs Adapted from: Schmidt et al. Soc Neurosci Abstr. 1998;24(2):2177

27. CATIE Trial Design Phase 2 Phase 3 Phase 1* Double-blind, random treatment assignment Participants choose either the clozapine or the ziprasidone pathway Participants choose one of the following open-label treatments Olanzapine Clozapine (Open-label) • Clozapine • Fluphenazine decanoate • Olanzapine • Perphenazine • Quetiapine • Risperidone • Ziprasidone • 2 of the above antipsychotics R Olanzapine, Quetiapine, or Risperidone Quetiapine 1600 Participants With Schizophrenia R Risperidone Ziprasidone R Olanzapine, Quetiapine, or Risperidone Ziprasidone No one assigned to same drug as in Phase 1 Perphenazine Responders stay on assigned medication for duration of 18-month treatment period. CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; *Phase 1A: participants with tardive dyskinesia do not get randomized to perphenazine; Phase 1B: participants who fail perphenazine will be randomized to an atypical agent (olanzapine, quetiapine, or risperidone) before they are eligible for Phase 2.

28. Current data are conflicting on the comparative effectiveness of antipsychotic therapy. Most studies comparing effectiveness of antipsychotic agents have design limitations that prevent the generalizability of conclusions. • The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project is a large-scale nonindustry-funded naturalistic research project to evaluate the clinical effectiveness of various atypical and typical antipsychotics in the treatment of schizophrenia.1,2 • Phase 1 of the study is a double-blind clinical trial in which patients are randomized to receive an atypical antipsychotic (olanzapine, quetiapine, risperidone, or ziprasidone) or perphenazine, a midpotency typical antipsychotic. If the initially assigned medication is not effective, patients may choose one of the following Phase 2 trials: • Randomization to open-label clozapine or double-blind treatment with an atypical antipsychotic that the patient has not yet received • Double-blind randomization to ziprasidone or another atypical antipsychotic that the patient has not yet received • If the Phase 2 study drug is discontinued, subjects may enter Phase 3, in which clinicians help subjects select an open-label treatment based on their experiences in Phases 1 and 2.

29. Comparing Different Atypicals • Patients in olanzapine and risperidone arms less likely to have had to switch • 23% of olanzapine patients did not switch • 18% of risperidone patients did not switch • 5% of quetiapine patients did not switch • Ziprasidone ?? • Quetiapine and ziprasidone were clearly under-dosed (?? Risperidone)

30. What CATIE (Schizophrenia) Tells Us • Even with atypicals, treatment response in schizophrenia still unsatisfactory • Overall 74% discontinuation over 18 months • Median discontinuation at 6 months • All agents pose challenges in terms of balancing efficacy and tolerability(Different for different agents) • Typicals: EPS • Olanzapine: weight gain/metabolic • Risperidone: EPS vs efficacy • Quetiapine: sedation/anticholinergic versus efficacy • Ziprasidone: GI/activation vs efficacy

31. 思覺失調症患者之心理治療

32. 目標是 • 承認生病的事實 • 認清疾病的本質 (比如幻聽等症狀etc) • 察覺症狀與個人困難的關聯性 • 察覺症狀有時被用來解決痛苦與衝突 • 個案不再將自己的不幸歸因於別人的不當對待, 而是自己負起接受治療 照顧自己健康的角色

33. General technical interventions • Establishing a relationship with the patient---症狀可能影響rapport建立, 病患可能多疑, 情感淡漠 • Elucidating the patient’s experience---傾聽, 澄清及回應患者的(幻覺)經驗及情感, 幫助患者接受/忍受, 進一步發展copingskills

34. Tolerating the mobilized transference and countertransference---through “projective identification”, patients project their unwanted parts onto the therapist; “holding” and “containment” of the therapist; the patient again would identify with the therapist for better coping • Integrating the patient’s experience into an expanded perspective of the self---盡量不詮釋 “content”, 而是詮釋阻抗, 防衛機轉, 症狀與痛苦的關聯