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」

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
Rajiv Tandon, M.D.
2001 Pfizer Talk 1

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 5 years later (same subjects)
STG, superior temporal gyrus; DLPFC, dorsolateral prefrontal cortex
0.0001
0.0005
0.001
0.005
0.01
0.05
p value
精神分裂症大腦逐漸病變, Gray matter逐漸loss
上面MRI試驗發現~~~相較於正常人(n=12), Early onset schizophrenia(n=12)大腦的Grey matter快速的流失;最早出現的缺損是在 parietal brain regions (主掌 視覺和關聯性思考的部位),之後更擴散到temporal lobes, 以及prefrontal cortices
下面MRI, 發病5年後, Grey matter loss缺損會越來越嚴重
Medication: Risperdal, clozapine
SUS
Thompson et. Al; PNAS of the USA,98(20): , 2001.
SUS-

7. 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
-0.2
Excessive decrease in superior frontal grey matter density in patients
Number of hospitalizations during scan-interval
-0.15
-0.1
-0.05
0.05 1 2 3 4 5 6 7 8
大腦灰質密度會隨著住院次數增加而降低
n=92; p=0.03
SUS
Van Haren et al. Neuropsychopharmacology 2007;32:2057–2066
SUS-

8. EUFEST Study: 33% to 72% FEP 於一年內中斷藥物治療
Time to treatment discontinuation
Haloperidol
Ziprasidone
Amisulpride
Olanzapine
Quetiapine
First-episode schizophrenia病人停止服藥的比率相當高
比率從 40% ~ 72%, 從歐洲大型臨床試驗, 針對First-episode schizophrenia所做的研究發現
不管是傳統的抗精神病藥物(ex.Haloperidol) or 新一代抗精神病藥物(ex. Olanzapine)
都有很高的停止服藥比率
Randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries.
Eligible patients were aged years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder.
498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride ( mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine ( mg per day; n=104), or ziprasidone ( mg per day; n=82); follow-up was at 1 year.The primary outcome measure was all-cause treatment discontinuation
The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI ]), olanzapine (HR 0.28 [ ]), quetiapine (HR 0.52 [ ]), and ziprasidone (HR 0.51 [ ]). However, symptom reductions were virtually the same in all the groups, at around 60%.
FEP: First Episode Patient
EUFEST: European First Episode Schizophrenia Trial
Kahn et al. Lancet 2008; 371: 1085–97
MKT-INV SUS-TW-0018
SUS-

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)
Rajiv Tandon, M.D.
2001 Pfizer Talk 1

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。

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)
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 Receptor Differences 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
Rajiv Tandon, M.D.
2001 Pfizer Talk 1

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
Antipsychotic therapy is the mainstay of treatment for schizophrenia. Before the 1950s, most treatments for psychotic conditions were essentially physical treatments such as electroconvulsive therapy, insulin shock, hospitalization, isolation, and/or physical restraint. The introduction of chlorpromazine in 1950 inaugurated the modern era of psychopharmacology and revolutionized the treatment of psychotic conditions.1 Chlorpromazine was followed in the 1960s by a number of agents including haloperidol, fluphenazine, thioridazine, loxapine, and perphenazine, which had similar pharmacologic activity.1,2 These agents essentially exert antipsychotic activity via antagonism at the dopamine type 2 receptor (D2) and are often classified as typical, conventional, or first-generation antipsychotics. During dopaminergic antagonism, these agents reduced psychotic symptoms but also produced adverse effects, notably extrapyramidal symptoms (EPS), and had minimal impact on negative, cognitive, and mood symptoms.
In the late 1980s, the first atypical antipsychotic, clozapine, was introduced. Other atypical—or second-generation—antipsychotics including risperidone, olanzapine, quetiapine, and ziprasidone later became available.1,2 Compared with typical antipsychotics, the atypical agents are characterized by reduced risk for EPS and improved activity on negative, mood, and cognitive symptoms. This is likely because atypical antipyschotics exert antagonist activity not only at the D2 receptor but also at the serotonin (5-HT2) receptors.
The most recently introduced atypical antipsychotic is aripiprazole. Aripiprazole has a unique pharmacologic profile that differs from other atypical antipsychotics in that it is a partial dopamine agonist—a functional agonist in hypodopaminergic states and functional antagonist in hyperdopaminergic states.3
References: 1. Kapur S, Remington G. Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med. 2001;52: ; 2. Worrel JA, Marken PA, Beckman SE, Ruehter V. Atypical antipsychotic agents: a critical review. Am J Health Syst Pharm. 2000;57: ; 3. Bowles TM, Levin GM. Aripiprazole: a new atypical antipsychotic drug. Ann Pharmacother. 2003;37:
Risperidone
Olanzapine Quetiapine Ziprasidone
Chlorpromazine
Clozapine Zotepine Amisulpride
Aripiprazole
ECT=electroconvulsive therapy.

25. Clinical Implications of Blockade of Various Receptors by Antipsychotics
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

26. Comparative Pharmacology of Atypical Antipsychotic Drugs
5-HT2A a1 a2 D1 D2 D4
Haloperidol
Risperidone H1
5-HT2C
Olanzapine M1
Clozapine
5-HT1A
Quetiapine
Ziprasidone
5-HT1D
Rajiv Tandon, M.D.
2001 Pfizer Talk 1
Adapted from: Schmidt et al. Soc Neurosci Abstr. 1998;24(2):2177

27. CATIE Trial Design Phase 1* Phase 2 Phase 3
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
1600 Participants With
Schizophrenia
Quetiapine
Olanzapine, Quetiapine, or Risperidone R
Risperidone
Ziprasidone
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.
References: 1. Comparative effectiveness of antipsychotic medications in patients with schizophrenia. Clinical Antipsychotic Trials of Intervention Effectiveness. NIMH Contract #N01MH University of North Carolina at Chapel Hill. Available at: Accessed March 31, 2004; 2. Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29:15-31. R
Olanzapine, Quetiapine, or Risperidone
Ziprasidone
Perphenazine
No one assigned to same drug as in Phase 1
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)
Schizophrenia is a devastating and chronic disease. The majority of patients alternate between exacerbations and remissions and require long-term treatment with antipsychotics. A significant proportion of patients—about 80%—do not experience complete remission of their symptoms. The majority of patients have some response but continue to have residual symptoms.1 Furthermore, a large percentage of patients will relapse (an estimated 35% will relapse within 1 year and 58% within 2 years).2 Contributing greatly to relapse is nonadherence; 40% to 48% noncompliance rates are reported and can reach as high as 74% after 2 years of treatment.3
In addition, schizophrenia is associated with a high incidence of comorbid conditions. Approximately 30% to 40% of patients with schizophrenia have reported using illicit drugs or alcohol,4 and 50% to 90% are smokers.5 Moderate generalized cognitive impairment and sensory deficits are prevalent as well.5 Further, schizophrenia sufferers are at high risk for suicide; approximately 30% of schizophrenics have attempted suicide at least once, with 10% completing the attempt.6-8
Despite the 1% disease prevalence in the general population, schizophrenia poses a disproportionate disease burden. Patients with schizophrenia occupy 9% of all hospital beds, 11% of nursing home beds, and 40.3% of mental health facility beds.9 In addition, the disease has been estimated to cost (both direct and indirect costs from 1991 data) close to $65 billion a year in the United States.10 It is therefore important to select the most appropriate pharmacotherapy as well as to implement psychosocial interventions targeted to patient needs.
References: 1. Freedman R. Drug therapy: schizophrenia. N Engl J Med. 2002;349: ; 2. Weiden PJ, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull. 1995;21: ; 3. Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry. 2002;63: ; 4. Chouljian TL, Shumway M, Balancio E, et al. Substance use among schizophrenic outpatients: prevalence, course, and relation to functional status. Ann Clin Psychiatry. 1995;7:19-24; 5. Jeste DV, Gladsjo JA, Lindamer LA, Lacro J. Medical comorbidity in schizophrenia. Schizophr Bull ;22: ; 6. Gupta S, Black DW, Arndt S, Hubbard WC, Andreasen NC. Factors associated with suicide attempts among patients with schizophrenia. Psychiatr Serv. 1998;49: ; 7. Radomsky ED, Haas GL, Mann JJ, Sweeney A. Suicidal behavior in patients with schizophrenia and other psychotic disorders. Am J Psychiatry.1999;156: ; 8. Caldwell CB, Gottesman II. Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophr Bull. 1990;16: ; 9. Worrel JA, Marken PA, Beckman SE, Ruehter VL. Atypical antipsychotic agents: a critical review. Am J Health Syst Pharm ;57: ; 10. Wyatt RJ, Henter I, Leary MC, Taylor E. An economic evaluation of schizophrenia– Soc Psychiatry Psychiatr Epidemiol ;30:

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
Schizophrenia is a devastating and chronic disease. The majority of patients alternate between exacerbations and remissions and require long-term treatment with antipsychotics. A significant proportion of patients—about 80%—do not experience complete remission of their symptoms. The majority of patients have some response but continue to have residual symptoms.1 Furthermore, a large percentage of patients will relapse (an estimated 35% will relapse within 1 year and 58% within 2 years).2 Contributing greatly to relapse is nonadherence; 40% to 48% noncompliance rates are reported and can reach as high as 74% after 2 years of treatment.3
In addition, schizophrenia is associated with a high incidence of comorbid conditions. Approximately 30% to 40% of patients with schizophrenia have reported using illicit drugs or alcohol,4 and 50% to 90% are smokers.5 Moderate generalized cognitive impairment and sensory deficits are prevalent as well.5 Further, schizophrenia sufferers are at high risk for suicide; approximately 30% of schizophrenics have attempted suicide at least once, with 10% completing the attempt.6-8
Despite the 1% disease prevalence in the general population, schizophrenia poses a disproportionate disease burden. Patients with schizophrenia occupy 9% of all hospital beds, 11% of nursing home beds, and 40.3% of mental health facility beds.9 In addition, the disease has been estimated to cost (both direct and indirect costs from 1991 data) close to $65 billion a year in the United States.10 It is therefore important to select the most appropriate pharmacotherapy as well as to implement psychosocial interventions targeted to patient needs.
References: 1. Freedman R. Drug therapy: schizophrenia. N Engl J Med. 2002;349: ; 2. Weiden PJ, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull. 1995;21: ; 3. Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry. 2002;63: ; 4. Chouljian TL, Shumway M, Balancio E, et al. Substance use among schizophrenic outpatients: prevalence, course, and relation to functional status. Ann Clin Psychiatry. 1995;7:19-24; 5. Jeste DV, Gladsjo JA, Lindamer LA, Lacro J. Medical comorbidity in schizophrenia. Schizophr Bull ;22: ; 6. Gupta S, Black DW, Arndt S, Hubbard WC, Andreasen NC. Factors associated with suicide attempts among patients with schizophrenia. Psychiatr Serv. 1998;49: ; 7. Radomsky ED, Haas GL, Mann JJ, Sweeney A. Suicidal behavior in patients with schizophrenia and other psychotic disorders. Am J Psychiatry.1999;156: ; 8. Caldwell CB, Gottesman II. Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophr Bull. 1990;16: ; 9. Worrel JA, Marken PA, Beckman SE, Ruehter VL. Atypical antipsychotic agents: a critical review. Am J Health Syst Pharm ;57: ; 10. Wyatt RJ, Henter I, Leary MC, Taylor E. An economic evaluation of schizophrenia– Soc Psychiatry Psychiatr Epidemiol ;30:

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coping skills

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