长效药物治疗.ppt

1、,Features of Schizophrenia,Social/Occupational Dysfunction Work Interpersonal relationships Self-care,Positive Symptoms Delusions Hallucinations Disorganized speech Catatonia,Negative Symptoms Affective flattening Alogia Avolition Anhedonia Social withdrawal,Cognitive Deficits Attention Memory Execu

2、tive functions(eg, abstraction),ComorbidSubstance Abuse,Mood Symptoms Depression Hopelessness Suicidality Anxiety Agitation Hostility,Maguire GA. Am J Health-Syst Pharm. 2002;59:S4-S11.,Brain volume changes in first-episode schizophrenia: a 1-year follow-up study,First-episode schizophrenia (n=34) a

3、nd matched healthy controls (n=36) MRI obtained at inclusion and after 1 year Outcome measured at 2 years Total brain volume and cerebral grey volume significantly decreased and lateral ventricle volume significantly increased in patients compared with controls Decrease in global grey matter volume

4、significantly correlated with outcome and, independent of that, with higher cumulative dosage of antipsychotic medication,MRI, magnetic resonance imaging,Adapted from Cahn et al. Arch Gen Psychiatry 2002;59:100210,MRI Schematic of Progression in Schizophrenia,First Episode Second Episode Third Episo

5、de Fourth Episode,Ventricular enlargement associated with poor outcome patients Longer duration of treatment associated with less ventricular enlargement over time,WHAT PART OF THE BRAIN TISSUE IS LOST IN SCHIZOPHRENIA ?,Atrophic Neuropil Changes in Schizophrenia,Shrinkage of the Brain in Schizophre

6、nia:Its in the Neuropil !,dendrite length by 50% in the number and size of of dendritic spines in the size contraction of neurite extension in # of glial cells Black et al, 2004 Glantz and Lewis, 2000,Copyright restrictions may apply.,Glantz, L. A. et al. Arch Gen Psychiatry 2000;57:65-73.,Brightfie

7、ld photomicrographs illustrating Golgi-impregnated basilar dendrites and spines on dorsolateral prefrontal cortex layer 3 pyramidal neurons from normal control subject 390 (A) and 2 subjects with schizophrenia (subjects 410 B and 466 C),Brain RepairIn Schizophrenia,NEUROPLASTICITY,Dendritic spines S

8、ynaptic remodeling Axonal sprouting Long-term potentiation Neurite extension Synaptogenesis Neurogenesis (neurons and glia),Animal Studies of Neurogenesis with Antipsychotics,First Generation Antipsychotics Several rat studies found no effect of haloperidol on neurogenesis: Haloperidol was actually

9、found to be neurotoxic, inducing apoptosis and neuronal cell death,Nasrallah HA, 2008 ,Animal Studies of Neurogenesis with Antipsychotics,Second-Generation Antipsychotics In contrast to haloperidol, several atypical antipsychotics (except for clozapine!) were reported to stimulate neurogenesis in ra

10、ts Olanzapine Risperidone Paliperidone Quetiapine Clozapine Aripiprazole: no studies Ziprasidone: no studies Nasrallah HA, 2008 ,OLFACTORY NEUROEPITHELIUM DATA,Nasrallah et al, ACNP Poster, December 2006,MRI Human Studies of Antipsychotics and Neuroplasticity,First generation antipsychotic: induced

11、hyperplasia in the striatum and in the substantia nigra (Konradi et al, 2001) Second generation antipsychotics: Olanzapine preserves grey matter volume decreases over 1-2 years while haloperidol does not Mean whole brain volume loss: - 3.7 cc vs. - 12.8 cc Risperidone treatment associated with large

12、r white matter volume than fluphenazine decanoate on placebo (Bartzokis et al, 2007). Authors speculate that risperidone stimulate the genesis of glia. Both risperidone and fluphenazine had lower grey matter volume than placebo. grey matter in left caudate and nucleus accumbens Olanzapine and Quetia

13、pine NAA (neuronal marker) in first episode manic patients, using MR Spectroscopy,Nasrallah HA, 2008 ,Effects of Antipsychotics on Neurotropic Factors in Schizophrenia,A growing literature confirms that neurotropins such as NGF (nerve growth factor) and BDNF (brain-derived neurotropic factor) are de

14、creased in drug-nave schizophrenia (Buckley et al, Schiz Res 2007) Neurotropins play a key role in neuroplasticity and in neuroprotection against apoptosis (programmed cell death) Thus, it is reasonable to assume that the deficit of NGF and BDNF in schizophrenia is related to loss of brain tissue vi

15、a apoptosis,Differential Effects of Typical and Atypical Antipsychotics on Neurotropins in Schizophrenia,Haloperidol causes pronounced reductions in NGF and BDNF and that reduction can be reversed by olanzapine or risperidone Unmedicated first-episode psychosis: NGF is reduced by 60% compared to hea

16、lthy controls. Treatment with haloperidol does not change this low level while atypical AP treatment increases NGF closer to normal levels,Nasrallah HA, 2008 ,Differential Effects of Typical and Atypical Antipsychotics on Neurotropins in Schizophrenia,Ziprasidone increases NGF acutely in rats but th

17、at effect faded after chronic exposure Quetiapine stimulates BDNF expression and reversed stress-induced decrease of BDNF in rat hippocampus Quetiapine significantly increases BDNF mRNA expression in the neocortex and hippocampus of rats even in the absence of stress No studies have been done yet wi

18、th aripiprazole,Nasrallah HA, 2008 ,THUS, UNLIKE CONVENTIONALS, ATYPICAL ANTIPSYCHOTICS HAVE BEEN SHOWN TO BE NEUROPROTECTIVE I.E. ATYPICALS CAN PREVENT PROGRESSIVE BRAIN TISSUE LOSS ASSOCIATED WITH PSYCHOSIS AND STIMULATE NEURITE EXTENSION, NEUROGENESIS AND CELL SURVIVAL,Differential effects of lon

19、g-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus,Anilkumar Pillai, Alvin V. Terry, Jr., and Sahebarao P. Mahadik Schizophrenia Research 82:95-106, 2006,Whole-Brain Gray Matter MRI Volumes for Patients by Treatment Group and for Healthy

20、Volunteers: Effects of Atypical VS. Typical antipsychotics (Baseline, Week 12, and Week 52) Lieberman JA et al: Arch Gen Psychiatry 2005,Pairwise analyses: LS mean changes in volume of the whole-brain gray matter in the haloperidol group differed significantly from that of olanzapine-treated patient

21、s (week 12, p0.001; week 52, p0.008) and healthy volunteers (week 12, p0.001; week 52, p0.003) at each time-point.,Risperidone in first-episode psychosis: A longitudinal, exploratory voxel-based morphometric study,Ragy R. Girgis, Vaibhav A. Diwadkara, Jeffrey J. Nutche, John A. Sweeney, Matcheri S.

22、Keshaven, and Antonio Y. Hardan Schizophrenia Research 82:89-94, 2006,Change in cerebral gray matter volumes with one month of antipsychotic treatment in patients hospitalized for acute exacerbation of chronic schizophrenia (no medication for 2 months),Garver et al. 2005,POOR ADHERENCE IN SCHIZOPHRE

23、NIA : THE MAJOR CAUSE OF RELAPSE and RELAPSE IS THE MOST LIKELY CAUSE OF DETERIORATION IN SCHIZOPHRENIA,Effect Sizes of 10-Second Generation Antipsychotics,-0.30,-0.20,-0.10,0.00,0.10,0.20,0.30,0.40,0.50,0.60,0.70,Clozapine,Amisulpride,Risperidone,Olanzapine,Zotepine,Sertindole,Aripiprazole,Quetiapi

24、ne,Ziprasidone,Remoxipride,Effect Size (d),Davis et al, Arch Gen Psychiatry,03,Availability of Antipsychotic Medication: One-Year Naturalistic Study,Mahmoud RA et al. Poster presented at: 36th Annual Meeting of the ACNP;December 8-12; Kamuela, Hawaii; Data on file, Janssen Pharmaceutica Products, L.

25、P. 1997.,Mean number of days with no therapy,The risk for psychotic relapse is high,104 first-episode schizophrenia patients *Year(s) since previous episode Confidence Interval,Robinson D, et al. Arch Gen Psychiatry 1999;56:2417,Prolongation of Time to Remission with Successive Psychotic Relapses,Da

26、ys to Remission,Adapted from Lieberman, et al. J Clin Psy, 1996, Denial of illness (anosognosia) Cognitive impairment Memory functions Executive frontal functions Negative symptoms Lack of initiative Lack of motivation Side effects of medications Substance abuse Erratic/partial compliance is human n

27、ature!,SCHIZOPHRENIA Why Poor Compliance is a Major Problem,SCHIZOPHRENIA,The grave consequences of inconsistent compliance: Medical: Psychotic relapse 2Kane, 1995,Cumulative Years of Treatment,% Patients with TD,70 60 50 40 30 20 10 0,123456,1-Year Incidence of Tardive Dyskinesia with Atypical vs.

28、Conventional Antipsychotics,Kane, 1995; Jeste et al, 1995; Yeung et al, 2001,Percept study : All psychiatrists expected their patients to prefer tablets,Administration form of first choice:,Patients (n=92),Psychiatrists (n=14),Hovens et al Schizophrenia Res 2006;81(suppl) 84; A120,1-Year, Open-Label

29、 Study,RIS-INT-57,RISPERDAL CONSTA: 1-Year Open-Label Trial in Stable Patients,*P 0.001.Fleischhacker WW et al. Poster presented at: Annual Meeting of the ACNP; December 8-14, 2001; Waikoloa, Hawaii.,Change in PANSS Total Score*,COST EFFECTIVENESS OF LONG-ACTING RISPERIDONE CONSTA,Chu et al, 2005a:

30、Canadian 1-year prospective study The need for hospitalization: decreased from 38% to 12% Chu et al, 2005b: Retrospective Canadian study Only 4.3% of patients required hospitalization of after taking Risperidone Consta, compared to 50.7% the year before. Also, the use of anxiolytics and anticholiner

31、gics decrease by 30%. Eriksson et al, 2003: Swedish multi-center study Hospitalization decreased by 38% Annual cost savings: average of $5,500 per patient Young and Taylor, 2006: Risperidone Consta did not reduce hospitalization rates compared to oral antipsychotic treatment. Patel et al, 2006: Pati

32、ents who discontinued long-acting Risperidone Consta were 3.08 times (odds ratio) more likely to be hospitalized than those who stayed on the injections.,Remission Criteria for Schizophrenia,Andreason, Carpenter, Kane, Lasser, Marder and Weinberger Am J Psychiatry 2005; 441-449 A score of 6 months:

33、P1:Delusions P2:Conceptual disorganization P3:Hallucinations G9:Unusual thought content G5:Mannerisms and Posturing N1:Blunted affect N4:Passive/apathetic social withdrawal N6:Lack of spontaneity and flow of conversation,Case I,34 y.o. single male, living in a group home Dx: paranoid schizophrenia s

34、ince age 16 Sxs: auditory hallucinations, TV actors talk to him, paranoid delusions, disorganized thinking Many relapses due to erratic compliance At age 28, switched from haloperidol to oral risperidone but better tolerability, his poor compliance continued,Case I (cont.),Consented to participate i

35、n a 12-week Risperidone Consta FDA trial Responded well and agreed to enter the open-label extension phase, 25 mgs IM Q 2 wks Patient became very stable (symptom-free) with no recurrences for 3 years. His PANSS dropped from 85 to 49.,Case I (cont.),In the second year on Risperidone Consta, he decide

36、d to return to school and get his GED which he did in 9 months. He then applied to a community college to study history. His family have been very pleased with his significant and prolonged improvement and have reintegrated him into the family Over the next three years, the patient shows full affect

37、, good judgment and insight, motivation, and has returned to dating and socializing.,Case II,24 y.o. single white male, lives with his mom Dx: Chronic Schizophrenia since age 17 Sxs: Hears voices talking about him. Suspicious about people wanting to harm him. Withdrawn and isolated. Frequently abuse

38、s marijuana laced with formaldehyde, as well as alcohol. Was admitted and treated with olanzapine and improved significantly over 9 weeks but gained 20 lbs.,Case II (cont.),Immediately following discharge, he discontinued olanzapine and returned to marijuana. Auditory hallucinations and paranoid ide

39、as returned along with bizarre behavior Was readmitted and offered to participate in a 12-week FDA trial of Risperidone Consta which he consented to and later stayed in the extension trial. His PANSS dropped from 83 to 56 after about a year on Risperidone Consta. He looked brighter and interacted ap

40、propriately and had insight that he no longer has psychotic symptoms. He started doing part-time yard work,Case II (cont.),In the second year on RC, he got a full-time job at Wendys and did very well. He developed a close relationship with a female co-worker. He no longer abused marijuana or alcohol

41、 because “drugs are bad for you”. Is happy with his life. Moved from his mothers house to his own apartment and his girlfriend moved in with him. His PANSS at the end of 4 years was 48,First-line treatment with long-acting risperidone in patients with first-episode psychosis: 12 months safety and ef

42、ficacy results,24 months Open study Single centre Efficacy and safety of RLAI First episode schizophrenia Pre-specified 12-month analysis,Emsley R, et al. 5th International conference on early psychosis 2006. Poster 0390,Clinical response,Percentage of patients achieving clinical response*,Emsley R,

43、 et al. 5th International conference on early psychosis 2006. Poster 0390,*20% or 50% reduction in PANSS scores,Stopping medication is the most powerful predictor of relapse,Gitlin et al. Am J Psychiatry 2001;158:183542,1.0 0.8 0.6 0.4 0.2 0,0122436486072,Patients without psychotic symptomexacerbati

44、on or relapse (%),Week,Remaining well,Relapsed,Accurate assessment of compliance is difficult for patients with schizophrenia,Two separate studies found that compliance is overestimated - by patient (left) phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, qu

45、etiapine, or risperidone) before eligibility for phase 2.,Stroup TS et al. Schizophr Bull. 2003;29:15-31.,CLOZAPINE,Primary Outcome Measure:All-Cause Treatment Discontinuation,All-Cause Discontinuation,Efficacy,Tolerability,Clinician Input,Patient Input,Treatment Discontinuation: All Causes,Lieberma

46、n JA et al. N Engl J Med. 2005;353:1209-1223.,Percentage of Subjects,Ziprasidone,Risperidone,Quetiapine,Olanzapine,Perphenazine,N=257,N=330,N=329,N=333,N=183,CATIE Schizophrenia Study,Modal Dose Ziprasidone 112.8mg Risperidone 3.9mg Quetiapine 543.4mg Olanzapine 20.1mg Perphenazine 20.8mg,Overall Ra

47、tes of Discontinuation by Reason in ITT Population (n=1432),(Note: administrative is included in all-cause but not in any of the other categories),Treatment Discontinuation: Intolerable Side Effects,Lieberman JA et al. N Engl J Med. 2005;353:1209-1223.,Percentage of Subjects,Ziprasidone,Risperidone,

48、Quetiapine,Olanzapine,Perphenazine,N=257,N=330,N=329,N=333,N=183,CATIE Schizophrenia Study,Modal Dose Ziprasidone 112.8mg Risperidone 3.9mg Quetiapine 543.4mg Olanzapine 20.1mg Perphenazine 20.8mg,White Matter Plasticity and Enhanced Remyelination in the Maternal CNS Christopher Gregg et al, 2007) (

49、Prolactin repairs white matter) Myelination, the process in which oligodendrocytes coat CNS axons with a myelin sheath, represents an important but poorly understood form of neural plasticity that may be sexually dimorphic in the adult CNS. Remission of multiple sclerosis during pregnancy led us to

50、hypothesize that remyelination is enhanced in the maternal brain. Here we report an increase in the generation of myelin-forming oligodendrocytes and in the number of myelinated axons in the maternal murine CNS. Remarkably, pregnant mice have an enhanced ability to remyelinate white matter lesions.

51、The hormone prolactin regulates oligodendrocyte precursor proliferation and mimics the regenerative effects of pregnancy. This suggests that maternal white matter plasticity imparts a striking ability to repair demyelination and identifies prolactin as a potential therapeutic agent,2007 Feb 21;27(8)

52、:1812-23.,White Matter Tractography from 3T Magnet,(Park, 2004),DTI Findings in Schizophrenia,Prefrontal Lobe (Buchsbaum et al 1998) Whole White Matter (Lim et al 1999; Minami et al 2003) Temporal Lobe (Ardekani et al 2003) Uncinate Fasciculus (Burns et al 2003; Kubicki et al 2002) Cingulum Bundle (

53、Kubicki et al 2003; Sun et al 2003; Wang et al 2004) Arcuate Fasciculus (Burns et al 2003) Corpus Callosum (genu) (Agartz et al 2001; Ardekani et al 2003; Foong et al 2000; Foong et al 2002) Internal Capsule (Buchsbaum et al 1998),A Randomized, Double-Blind, 52-Week Comparison of Olanzapine, Quetiapine, and Risperidone,Comparison of Atypicals in First-Episode Psychosis (CAF),CAF All-Cause Treatment Discontinua