Demenza

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Utilizzo di antipsicotici nelle modificazioni comportamentali nel paziente con demenza

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Demenza

  1. 1. Treatment  of  behavioral  symptoms  related  to  demen4a   Behavioral  symptoms  in  Alzheimer  disease  (AD)  and   other  types  of  demen8a  are  extremely  common  and   o;en  much  more  troubling  than  amnes8c  symptoms.   This  topic  will  review  the  causes  and  treatment  of   behavioral  disturbance  and  symptoms  related  to   demen8a  
  2. 2. An4psycho4c  drugs   Atypical  neurolep4cs  have  been  the  agents  of  choice  for  trea4ng  hallucina4ons   in  pa4ents  with  demen4a.  However,  these  drugs  may  increase  mortality,  and   are  not  approved  for  the  treatment  of  behavioral  disorders  in  pa8ents  with   demen8a  by  the  US  Food  and  Drug  Administra8on  (FDA).  Nonetheless,  their   benefits  o;en  s8ll  outweigh  their  risks  in  pa8ents  with  demen8a  when   treatment  of  hallucina8ons  and  delusions  is  cri8cal.  In  the  absence  of  other   effec4ve  agents,  we  con4nue  to  use  them  cau4ously,  a>er  informing  the   pa4ents  and  families  of  the  poten4al  risks  Typical  an4psycho4cs  —  A  systemic  review  of  typical  an8psycho8cs  included  two  meta-­‐analyses  of  12  trials  plus  two  addi8onal  studies  of  haloperidol,  thioridazine,  thiothixene,  chlorpromazine,trifluoperazine  and  acetophenazine,  and  concluded  that,  in  the  aggregate,  there  was  no  clear  evidence  of  benefit  for  these  agents  in  pa8ents  with  demen8a  [42].  A  Cochrane  review  concluded  that  haloperidol  may  help  control  aggression,  but  not  other  neuropsychiatric  manifesta8ons  of  demen8a  [43].  No  trials  compared  agents  with  one  another  Atypical  an4psycho4cs  —  These  agents  include  clozapine,  olanzapine,  risperidone,  and  que4apine  and  have  been   somewhat  more  extensively  studied.  Two  independently  conducted  systema8c  reviews  have  concluded  that  these  agents  have,  at  most  modest  efficacy  [42,44].  Of  seven  trials  studied,  four  found  a  sta8s8cally  significant  benefit  for   the  primary  endpoint  with  olanzapine  or  risperidone;  there  were  no  studies  of  clozapine  and  que8apine  for  this   indica8on  at  the  8me  of  this  analysis.  
  3. 3. CLASSIFICAZIONE  DEI  FARMACI  ANTIPSICOTICI  IN  TIPICI  ED  ATIPICI  TIPICI   ATIPICI  Feno8azine  Clorpromazina  -­‐  Largac4l   Benzamidi  Promazina  Talofen     Sulpiride  –  Dobren  Tioridazina    -­‐  MellereQe  -­‐Melleril   Dibenzoxazepine  Flufenazina  -­‐    Anatensol,  Moditen  Depot   Clozapina  -­‐  Leponex  Tioxanteni   Olanzapina  -­‐  Zyprexa  Zuclopen8xolo  -­‐  Clopixol   Altri  compos8  Bu8rrofenoni   Risperidone  -­‐Risperidal  Aloperidolo  -­‐    Haldol  -­‐  Serenase     Zipraxidone  Difenilbu8lpiperidine  Pimozide  -­‐  Orap  
  4. 4. Side  effects   The  choice  of  specific  an8psycho8c  drug  used  to  treat  hallucina8ons  is  driven  by   drug  side  effects  such  as  seda8on  or  extrapyramidal  disturbances.  The  older  low   potency  typical(conven4onal)  neurolep4cs  (eg,  chlorpromazine  and  thioridazine)   are  highly  seda8ng,  and  their  an8cholinergic  ac8vity  can  worsen  memory  and   cogni8on.  High  potency  neurolep8cs  (eg,  haloperidol  and  fluphenazine)  are  associated  with  an  o;en  unacceptable  incidence  of  extrapyramidal  side  effects.  In  a  trial  of  haloperidol,  for  example,  there  was  a  high  rate  of  extrapyramidal  side  effects   and  decline  in  cogni8ve  func8on  even  at  rela8vely  low  doses  of  1  to  5   mg.Intravenous  haloperidol  has  been  associated  with  clinically  significant  QT   prolonga8on  requiring  addi8onal  precau8ons  regarding  its  use.  While  the  atypical  neurolep4cs  are  perceived  to  have  a  lower  incidence  of  adverse   effects,  this  may  be  true  only  with  low  doses.  Systema8c  reviews  and  clinical  trials   find  that  adverse  events  with  these  agents  in  pa8ents  with  demen8a  are  common  and  dose  related.  These  include  extrapyramidal  symptoms,  confusion,  somnolence,  and  falls.  The  addi8onal  risk  of  agranulocytosis  with  clozapine  and  the  necessity  for   frequent  blood  tests  make  this  agent  less  a`rac8ve.  
  5. 5. Mortality  risk  The  US  Food  and  Drug  Administra8on  (FDA)  reported  in   a  public  health  advisory  that  the  use  of  second   genera8on  an8psycho8c  medica8ons,  aripiprazole,   olanzapine,  que4apine,  and  risperidone,  for  the   treatment  of  behavioral  symptoms  in  elderly  pa8ents   with  demen8a  is  associated  with  increased  mortality   [49,50].  Their  findings  were  confirmed  in  an   independently  conducted  meta-­‐  analysis,  as  well  as  a  subsequent  randomized,  placebo-­‐controlled  study.  The   reported  odds  ra8o  for  increased  mortality  in  these   analyses  ranged  from  1.54  to  1.7.  
  6. 6. Clinical  use   Given  the  risk  of  increased  mortality  associated  with  the  use  of  atypical  neurolep8cs  in  elderly  pa8ents  with   demen8a  ,  we  reserve  their  use  for  pa8ents  who  have  neuropsychiatric  symptoms,  par4cularly  psychosis,  that   are  severe  and  debilita4ng  and  inform  pa4ents  and  families  of  the  risks.  There  is  o;en  no  good  alterna8ve.   Somnolence  is  also  concern  with  all  of  these  agents,  and  may  be  dose  limi8ng.   Olanzapine    (Zyprexa  cpr  2.5  ,  5,  10  mg  CLASSE  A  NOTA  A8  PIANO  TERAPEUTICO)    can  be  started  at  a  dose  of  2.5  mg  daily  and  4trated  up  to  a  maximum  of  5  mg  twice  a  day.  This  drug  appears  to   be  at  least  modestly  effec8ve  for  trea8ng  the  neuropsychiatric  symptoms  of  demen8a  in  pa8ents  with  AD  or   vascular  demen8a.  The  incidence  of  extrapyramidal  symptoms  is  low  at  this  dose.   Que4apine  (Seroquel  cpr  25,  50,  100,  150,  200,  300,  400  mg  CLASSE  A  NOTA  A8  PIANO  TERAPEUTICO)    is  an  alterna8ve,  star8ng  at  a  dose  of  25  mg  at  bed4me  and  4tra4ng  up  to  a  maximum  of  75  mg  twice  a  day.   There  is  li`le  data  regarding  the  effec8veness  of  que8apine  in  this  seeng.   Risperidone  (Risperdarl  cpr1,2,3,4,mg  CLASSE  A  NOTA  A8  PIANO  TERAPEUTICO)   at  no  more  than  1  mg  daily  also  appears  to  be  at  least  modestly  effec8ve,  but  higher  doses  are  associated  with   increased  side  effects.   Treatment  should  be  maintained  only  if  benefits  are  apparent,  and  discon8nua8on  should  be  a`empted  at   regular  intervals.  
  7. 7. SUMMARY     AND    RECOMMENDATIONS    
  8. 8. Neuropsychiatric  symptoms  are  common  in  demen8a  and  contribute  to  nursing  home  admission  and  caregiver  stress.  When  a  pa8ent  develops  neuropsychiatric  symptoms,  the  first  step  is  to  rule  out  and  treat  a  medical  cause  or  superimposed  delirium  
  9. 9. Environmental,  behavioral,  and  other  nonpharmacologic  therapies  can  be  effec8ve  in  this   popula8on  and,  when  appropriate,  are  preferred  over  medica8ons,  which  have  a  high  rate  of   adverse  effects.     Cholinesterase  inhibitors  do  not  produce  clinically  significant  improvement  in  neuropsychiatric   symptoms  in  pa8ents  with  demen8a.  However,  many  such  pa8ents  are  s8ll  treated  with  these   drugs  because  of  modest  improvement  in  cogni8on.   An8psycho8c  agents  have  limited  efficacy  and  are  associated  with  increased  mortality  in  pa8ents  with  demen8a.  We  suggest  the  use  of  low  doses  of  olanzapine  or  que8apine  in  pa8ents   with  severe,  disabling  symptoms  a;er  informing  families  of  the  mortality  risk  (Grade  2B).  Short   term  use  when  possible,  with  regular  reassessments  of  risks  and  benefits,  is  advised.  A  trial  of  selec8ve  serotonin  reuptake  inhibitors  (SSRIs)  is  suggested  for  the  treatment  of  depression  in  Alzheimer  disease  (Grade  2C).  Citalopram  is  o;en  used  because  of  its  possible  addi8onal  benefits  for  neuropsychiatric  symptoms.  Sertraline  is  a  well  studied   alterna8ve  to  citalopram.  A  trial  of  trazodone  may  also  be  considered  to  treat   psycho8c  symptoms,  especially  when  they  interfere  with  sleep.  Tricyclics  should  be   avoided  because  of  side  effects  and  drug  interac8ons.  Agita8on  may  be  due  to   unrecognized  depression  and  respond  to  an  SSRI.  Because  of  the  risk  of  side  effects   with  long-­‐term  use,  we  recommend  reserving  benzodiazepines  for  acute  stressful   episodes  

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