Atipični antipsihotici kao stabilizatori raspoloženja - da ili ne.ppt
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Atipični antipsihotici kao stabilizatori raspoloženja - da ili ne.ppt
- 1. ATIPIČNI ANTIPSIHOTICI KAO STABILIZATORI RASPOLOŽENJA DA ili NE Vladimir Janjić Klinika za psihijatriju KC Kragujevac Fakultet medicinskih nauka Kragujevac Čedo Miljević Institut za mentalno zdravlje Beograd Medicinski fakultet Beograd
- 2. Po profesiji sam: 1. Psihijatar 2. Neuropsihijatar 3. Specijalista druge specijalnosti/lekar opšte prakse 4. Farmaceut 5. Ostalo (psiholog, soc. radnik, defektolog, med. sestra/tehničar...)
- 3. Hotel u kojem se trenutno nalazimo, zove se: 1. Hotel Šumarice 2. Hotel Zelengora 3. Hotel Kragujevac 4. Hotel Metropol 5. RITZ CARLTON
- 4. SPEKTAR BIPOLARNE SIMPTOMATOLOGIJE MANIJA Euforija Ideja veličine Impulsivnost Porast libida Nemir potreba za spavanjem DEPRESIJA Depresija Anksioznost Iritabilnost Hostilnost Violentnost Suicid Manična, depresivna ili mešana PSIHOZA • Sumanute ideje • Halucinacije • Senzorna hiperaktivnost KOGNICIJA • Bekstvo misli • Distraktibilnost • Slab uvid • Dezorganizacija • Konfuzija
- 5. MULTIDIMENZIONALNOST BAP-a Vieta & Goikolea 2005. Hipomanija Manija Depresija Rekurenca (manija) Subsindromalna depresija Remisija Epizoda sa mešanim simptomima
- 6. MKB- 10 POREMEĆAJI RASPOLOŽENJA F 31 PSYCHOSIS AFFECTIVA, TYPUS BIPOLARIS • F 31.0 Psychosis affectiva bipolaris, episodum hypomanicum • F 31.1 Psychosis affectiva bipolaris, episodum manicum non psychoticum • F 31.2 Psychosis affectiva bipolaris, episodum manicum psychoticum • F 31.3 Psychosis affectiva bipolaris, episodum deprresivum, gradus levi sive moderati • F 31.4 Psychosis affectiva bipolaris, episodum deprresivum, non psychoticum, gradus majoris • F 31. 5 Psychosis affectiva bipolaris, episodum deprresivum, psychoticum, gradus majoris • F 31.6 Psychosis affectiva bipolaris, episodum mixtum DSM- V BIPOLARNI I POVEZANI POREMEĆAJI •BIPOLARNI POREMEĆAJ, TIP I Klinički tok koji se karakteriše pojavom jedne ili više maničnih ili mešovitih epizoda. Često oboleli takođe imaju jednu ili više Velikih depresivnih epizoda •BIPOLARNI POREMEĆAJ, TIP II Klinički tok koji se karakteriše pojavom jedne ili više depresivnih epizoda kod obolelih koji su imali bar jednu hipomaničnu epizodu •CIKLOTIMNI POREMEĆAJ • BIPOLARNI I POVEZANI POREMEĆAJI TOKOM DRUGIH MEDICINSKIH STANJA
- 7. KONTRAVERZE I IZAZOVI LEČENJA BAP-a STABILIZATORI RASPOLOŽENJA Idealni stabilizator raspoloženja efikasan je u stanjima manije i depresije i sprečava cikliranje, tj. prelaz jednog stanja u drugo. EUTIMIJA terapija održavanja MANIJA •AP •BDZ •HIP ??? DEPRESIJA •AD •AP •BDZ •HIP ???
- 8. U mom kliničkom radu terapija izbora za akutnu maniju je: 1. Litijum 2. Valproat 3. Haloperidol 4. Atipični antipsihotik 5. Stabilizator + klasični antipsihotik 6. Stabilizator + atipični antipsihotik
- 9. Inhalator za lečenje astme sa opijumom
- 10. Savremeni vodiči za tretman BAP-a American Psychiatric Association (APA) British Association for Psychopharmacology Canadian Network for Mood and Anxiety Group ECNP Consensus Meeting March 2000 Nice Expert Consensus Guidelines Series Texas Medication Algorithm Project The Expert Cosensus Panel for Bipolar Disorders The World Federation of Societies of Biological Psy. Guidelines for the Biological Treatement of BAD
- 12. Akutna manija Prva linija Druga linija APA, 2002 i 2007 Litijum (Li)/Valproat (Vp)+AP Ili monoterapija Li, Vp, Olanzapin (Olz) Kombinovana th- 2 ili više lekova iz prve linije; EKT 2007 update- Li za maniju; Vp za mešanu epizodu, Karbamazepin (Kbz), Olz, Li/Vp+AP, EKT CANMAT, 2007 Litijum, Valproat Atipični AP Li/Vp+ AAP karbamazepin Karbamanzepin Okskarbamazepin EKT, Li+Vp Haldol NICE, 2006 Olanzapin, Risperidon Li/Vp (responderi) Li/Vpa + AAP WFSBP, 2003 Litijum Valproat Atipični AP Karbamazepin Kombinovana terapija- stabilizator + AP EKT TMAP, 2002 Litijum Valproat Olanzapin Kombinovana th- 2 leka prve linije
- 13. 68 RCT ukupno 16 073 pacijenata od 1.1.1980. do 25.11.2010. Haloperidol Risperidon Olanzapin Litijum Kvetiapin Aripriprazol Karbamazepin Asenapin Valproat Ziprasidon
- 16. Effective treatments for acute mania Lithium: 4 positive placebo-controlled RCTs, (0.6-1.4 mEq/L) Responders 49-53.3% for lithium vs 25-27.4% for placebo. (NNT=4) Bowden et al JAMA 1994 Mar 23-30; 271(12): 918-924, Bowden et al J Clin Psychiatry 2005 Jan; 66(1): 111-121. Kushner et al, Bipolar Disord 2006 Feb; 8(1): 15-27. Keck et al J Affect Disord 2009 Jan; 112(1-3): 36-49. Valproate: 4 positive, 1 negative placebo-controlled RCTs (85-150 micrograms/mL) Responders 48% vs. 25-35% of placebo (NNT= 4-8) Bowden et al JAMA 1994 Mar 23-30; 271(12): 918-924. Bowden et al.J Clin Psychiatry 2006 Oct; 67(10): 1501-1510. Tohen et al. The Journal of clinical psychiatry 2008 Nov; 69(11): 1776-1789 Hirschfeld et al. J Clin Psychiatry 2010;71:426-432 McElroy et al. 2010;J Clin Psychiatry 71:557-565 Carbamazepine: 2 positive placebo-controlled RCTS (8.9 microg/mL) Responders 41.5% vs. 22.4% under placebo. NNT=5 Weisler et al. J Clin Psychiatry 2004 Apr; 65(4): 478-484. Weisler et al. J Clin Psychiatry 2005 Mar; 66(3): 323-330. Lamotrigine: 2 unpublished negative RCTs (SCAA2008 and SCAA2009) (11). Fountoulakis et al Int J Neuropsychopharmacology 2008 Nov; 11(7): 999-1029. Gabapentin and topiramate: Negative RCT data Frye et al J Clin Psychopharmacol 2000 Dec; 20(6): 607-614. Kushner et al. Bipolar Disord 2006 Feb; 8(1): 15-27.
- 19. D1 D2 5-HT2A 5-HT1A A1 A2 H1 Risperidon Ziprasidon D2 D1 5-HT2A 5-HT1A A1 Haloperidol A2 H1 D1 D2 5-HT2A 5-HT1A A1 D1 D2 5-HT2A 5-HT1A A1 A2 H1 Klozapin D1 D2 5-HT2A A1 A2 H1 M Olanzapin Kvetiapin D1 D2 5-HT2A 5-HT1A A1 A2 H1 M Receptorski profili AP Goldstein, Int J Neuropsychopharmacol 2000
- 20. Atipični antipsihotici u lečenju akutne manične epizode LEK BROJ STUDIJA N ODGOVOR POREDJENJ. Risperidon 3 353 RIS: 58 MS:40% RIS=HL=Li RIS+MS>MS Ziprazidon 1 195 ZIP>PL Olanzapin 5 875 OL:66% PL:34% OL 54% VAL 42% OL 49% Li 38% OL+MS 68% MS: 45% OL>PL OL≥VAL OL≥Li OL+MS>MS Promena AP 16 2378 CAP: 85 CAP>PL CAP=Li=CBZ
- 21. Kvetiapin XR u terapiji BAP-a -netipičan atipičan antipsihotik- Bezbednost Efikasnost Farmakološki profil Adherenca Seroquel XR (extended release) – kvetiapin tablete sa produženim oslobađanjem Seroquel IR (immediate release) - kvetiapin ‘obične’ tablete
- 22. D1 D2 5-HT2A 5-HT1A A1 A2 H1 SEDACIJA KVETIAPIN REDUKCIJA PSIHOTIČNIH SIMPTOMA MANIJE -REDUKCIJA NEPSIHOTIČNIH SIMPTOMA MANIJE -POBOLJŠANJE KOGNICIJE REGULACIJA SNA, ANKSIOZNOSTI I DEPRESIVNOSTI NORKVETIAPIN-metabolit • Norepinefrin transporter (NET) antagonista • Redukuje depresivne simptome • Poboljšava antipsihotičko dejstvo • Povećava DA output u PFC
- 23. Day ‡ † ‡ ‡ -20 -15 -10 -5 0 0 7 14 21 Quetiapine XR (n=149) Placebo (n=159) ‡ † 50% YMRS redukcija YMRS 12 Odgovor Remisija Kvetiapine XR monoterapija poboljšava simptome manije već 4. dana Trial 004XR Cutler et al, 2008. †P<0.01; ‡P<0.001 vs. placebo. ITT, LOCF Patients (%) 0% 20% 40% 60% 80% YMRS total score: Mean change Mean daily dose quetiapine XR 603.8 mg.
- 24. Rano poboljšanje u maničnoj epizodi uočava se i pri primeni Kvetiapina kao dodatne terapije ‡ ‡ ‡ Yatham et al, 2004; Sussman et al, 2005. †P<0.01; ‡P<0.001 vs. placebo+Li/DVP. † † Odgovor Remisija 50% YMRS redukcija YMRS 12 Day 0 7 14 21 -20 -15 -10 -5 0 QTP+Li/DVP (n=185) Placebo+Li/DVP (n=185) Trials 99 + 100 (pooled data) ITT, LOCF Patients (%) 0% 20% 40% 60% 80% YMRS total score: Mean change Mean last week QTP dose in responders was 492 mg/day.
- 25. Atipični antipsihotici: Konzistentni monoterapijski efekti u maničnoj epizodi Promene u YMRS skoru u odnosu na placebo (mean and 95% CI) –13 –12 –11 –10 –9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 2 3 4 Pooled Monotherapy Drug Effects (random-effects model) Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Lithium Haloperidol Perlis et al, 2006. Dotted line on the left indicates pooled difference vs. placebo.
- 26. ZNAČAJ AP U TERAPIJI AKUTNE MANIJE •BRŽE DOSTIZANJE TERAPIJSKE DOZE •BRZ POČETAK DEJSTVA •MONOTERAPIJSKA ILI KOMBINOVANA PRIMENA •MOGUĆNOST PARENTERALNE PRIMENE •DELUJU NA PSIHOTIČNE SIMPTOME •REGULIŠU NESANICU •REDUKUJU PSIHOMOTORNU HIPERAKTIVNOST •DOBAR BEZBEDNOSNI PROFIL •META-ANALIZE POKAZUJU DA SU ANTIPSIHOTICI EFIKASNIJI OD STABILIZATORA RASPOLOŽENJA U TRETMANU AKUTNE MANIJE Stahl 2011; Sachs et al 2002; Zarate et al 2004; Tohen et al 2008; Cipriani et al 2011
- 27. U akutnoj fazi bipolarne depresije koristim antidepresive: 1. Da, kao monoterapija 2. Da, u kombinaciji sa stabilizatorom raspoloženja 3. Da, u kombinaciji sa atipičnim antipsihotikoma 4. Da, u kombinaciji sa satabilizatorom i atipičnim antipsihotikoma 5. Ne koristim
- 28. Opijum za novorođenčad Od ovih kapi deca, ali i odrasli, su veoma dobro spavali. Ne samo zbog opijuma, već i zbog 46% alkohola.
- 29. 47 Depression: APA Guidelines Executive Summary • First line for new episodes – Lithium [I] or lamotrigine [II] – In more severely ill patients, consider lithium plus antidepressant [III] – Consider ECT if life-threatening inanition, suicidality, psychosis [I] • Breakthrough episodes – Optimize primary agent [II] – Add lamotrigine [I], bupropion [II], or paroxetine [II] – Alternatives: another SSRI [II], venlafaxine or MAO-I [II] [I] Recommended with substantial clinical confidence [II] Recommended with moderate clinical confidence [III] May be recommended on the basis of individual circumstances American Psychiatric Association. Am J Psychiatry. 2002;159(suppl 4):1-50.
- 31. Effective treatments for acute bipolar depression Lithium: 1 negative placebo controlled RCT Young et al J Clin Psychiatry 2010;71:150-162 2 meta-analysis positive for divalproex with response rates 39.3% vs. 17.5% for placebo, and remission rates were 40.6% vs. 24.3%, with effect size d equal to 0.35 Bond et al. J Affect Disord 2010; 124:228-234,. Smith et al. J Affect Disord 2010; 122:1-9. Carbamazepine: 1 old positive small withdrawal study Ballenger et al. Am J Psychiatry 1980 Jul; 137(7): 782-790. Lamotrigine: 5 negative placebo controlled RCTs (SCA100223, SCA30924, SCA40910, SCAA2010 and SCAB2001) Goldsmith et al Drugs 2003; 63(19): 2029-2050
- 36. Atipični antipsihotici u lečenju akutne depresivne epizode LEK BROJ STUDIJA N ODGOVOR POREDJENJ. Amisulprid 4 1073 AMI 67% PL 33% AD 66% AMIS=AD>PL Sulpirid 7 372 SUL=PL Olanzapin 2 68 OL 48% AD 40% OL=AD Olanzapin/ Fluoksetin 3 413 OFC 72% PL 32% OL 50% LAM 40% OFC>PL/OL/LAM Risperidon 1 123 RIS 51% AMI/HAL 70% RIS<AMI/HAL
- 37. D1 D2 5-HT2A 5-HT1A A1 A2 H1 SEDACIJA KVETIAPIN REDUKCIJA PSIHOTIČNIH SIMPTOMA -REDUKCIJA DEPRESIVNIH I ANKSIOZNIH SIMPTOMA -POBOLJŠANJE KOGNICIJE REGULACIJA SNA, ANKSIOZNOSTI I DEPRESIVNOSTI NORKVETIAPIN-metabolit • Norepinefrin transporter (NET) antagonista • REDUKUJE DEPRESIVNE SIMPTOME!!! • Poboljšava antipsihotičko dejstvo • Povećava DA output u PFC
- 38. ***p<0.001 vs placebo for both active arms at all timepoints Calabrese et al. 2005; Thase et al. 2006. Change in MADRS score from baseline (ITT, LOCF) Improvement Nedelja BOLDER I (n=511) -20 -15 -10 -5 0 0 1 2 3 4 5 6 7 8 *** *** *** *** *** *** *** *** BOLDER II (n=467) Nedelja 0 1 2 3 4 5 6 7 8 *** *** *** *** *** *** *** *** Quetiapine 300 mg/d Placebo Quetiapine 600 mg/d . Kvetiapin – efikasan i kao monoterapija u BAP depresiji u 1. nedelji
- 39. 10 8 6 4 2 0 Kvetiapin XR u BAP depresiji – Nizak rizik od switcha u maniju* *Adverse event of mania/hypomania or YMRS total score ≥16 at 2 consecutive visits or last visit EMBOLDEN I and II; BOLDER I and II (pooled data) Trial 002XR Suppes et al, 2009b; Calabrese et al, 2009. Patients (%) QTP 300 mg (n=853) QTP 600 mg (n=859) Placebo (n=602) QTP XR 300 (n=137) Placebo (n=140) Safety
- 40. 5 1 -5 -4 -3 -2 -1 0 1 2 3 4 5 Trials with no statistical separation from placebo on primary endpoint Trials with statistical separation from placebo on primary endpoint 2 5 4 3 2 1 1 2 3 4 Quetiapine1-5 Olanzapine6 Lamotrigine7 Aripiprazole8 1. Calabrese et al, 2005; 2. Thase et al, 2006; 3. Young et al, 2008a; 4. McElroy et al, 2008; 5. Suppes et al, 2009b; 6. Tohen et al, 2003a; 7. Calabrese et al, 2008; 8. Thase et al, 2008; 9. Sachs et al, 2009. Kvetaipin monoterapija u BAP depresiji – najviše potvrda o efikasnosti Broj randomiziranih kliničkih studija 5 2 Ziprasidone9 5
- 41. MAUDSLEY PRESCRIBING GUIDELINES (2012) 1. Linija - KVETIAPIN 2. Linija - Li, VALPROAT 3. Linija - LAMOTRIGIN (kao dodatak stabilizatoru raspoloženja) 4. linija-AD+STABILIZATOR RASPOLOŽENJA (OFC, najbolja kombinacija) A 1 KVETIAPIN B 3 OLANZAPIN VALPROAT LAMOTRIGIN OFC LAM+Li WFSBP GUIDELINES (2010) PREPORUKE ZA LEČENJE DEPRESIVNE EPIZODE BAP-A
- 42. Terapiju održavanja BAP-a kontinuirano primenjujem: 1. manje od 6 meseci 2. do godinu dana 3. do 2 godine 4. do 5 godina 5. doživotno 6. u zavisnosti od broja epizoda i faza bolesti
- 43. Marijanijevo vino (1875) je bilo najpoznatije vino od koke tog vremena. Papa Leo XIII je uvek kod sebe imao jednu bocu ovog vina. Papa je proizvođača ovog vina, Anđena Marijanija, odlikovao Vatikanskom zlatnom medaljom. Marijanijevo vino
- 47. Effective treatments for bipolar maintenance treatment Lithium: Earlier maintenance placebo-controlled RCTs suggested lithium was effective for the prophylaxis against both mania and bipolar depression Dunner et al . Arch Gen Psychiatry 1976, 33(1):117-120. Prien et al. Hosp Community Psychiatry 1984, 35(11):1097-1098. Prien et al Arch Gen Psychiatry 1984, 41(11):1096-1104. Prien et al. Arch Gen Psychiatry 1973, 28(3):337-341. Prien et al. Arch Gen Psychiatry 1973, 29(3):420-425. Glen et al. Psychol Med 1984, 14(1):37-50. Latter maintenance placebo-controlled RCTs suggest that lithium is effective in the prevention of manic episodes but maybe not for depressive episodes Kane et al. Arch Gen Psychiatry 1982, 39(9):1065-1069. Bowden et al. Arch Gen Psychiatry 2000, 57(5):481-489. Bowden et al Arch Gen Psychiatry 2003, 60(4):392-400. Calabrese et al. J Clin Psychiatry 2003, 64(9):1013-1024. Calabrese et al. Biol Psychiatry 2006, 59(11):1061-1064. Goodwin et al. J Clin Psychiatry 2004, 65(3):432-441.
- 48. Effective treatments for bipolar maintenance treatment Divalproex: 1 negative 12-month ‘prophylactic’ study (negative for lithium as well) Bowden et al. Arch Gen Psychiatry 2000, 57(5):481-489. Lamotrigine: 2 12-month placebo controlled RCTs. Prevents depressive but not manic episodes. Response rate 57% for lamotrigine vs. 45% for placebo. NNT= 8 Bowden et al Arch Gen Psychiatry 2003, 60(4):392-400. Calabrese et al. J Clin Psychiatry 2003, 64(9):1013-1024. Carbamazepine: There is only one small old positive study Okuma et al Psychopharmacology (Berl) 1981, 73(1):95-96. Overall there are no strong data on the superiority of any agent versus another with the exception of lamotrigine for the prevention of depressive episodes.
- 49. Meta-analytic studies for the bipolar maintenance treatment A meta-analysis of 34 randomised and quasi-randomised controlled trials: - evidence for the efficacy of lithium, valproate and lamotrigine - lithium, olanzapine and aripiprazole against manic relapses - valproate, lamotrigine and imipramine against depressive relapses - little evidence to support the efficacy of combination therapy Beynon et al J Psychopharmacol 2009, 23(5):574-591. NNT for various agents varying from 3-8 Popovic et al Psychopharmacology (Berl) 213:657-667, 2010.
- 54. = at least 1 randomized controlled trial (RCT) showing significant effects = at least 1 RCT showing some effect = adequately powered, RCT evidence of a lack of significant effects = inadequately powered, uncertain, or no controlled data available Atipični Antipsihotici: Pregled Long-Term podataka u terapiji održavanja Dodatna ili monoterapija Index Epizode Odlaganje rekurence Bilo koje epizode Manija/Mešana Depresivna Olanzapine M Manija/Mešan Risperidone D i M Manija/Meša/ Remisija ? Quetiapine D i M Manija/Meša/ Depresija Ziprasidone D Manija/Mešan ? Aripiprazole M Manija/Mešan ? Asenapine - - ? ? ? Paliperidone - - ? ? ? ? Tohen et al, 2003b; Tohen et al, 2006; Keck et al, 2007; Vieta et al, 2008b; Vieta et al, 2008c; Young et al, 2008a; McElroy et al, 2008; Weisler et al, 2008; Suppes et al, 2009; Vieta et al, 2009.
- 55. Quetiapine (n=404) Placebo (n=404) Lithium (n=364) Time (weeks) Proportion of patients event free 1.0 0.0 0.6 0.8 0.2 0.4 0.5 0.7 0.1 0.3 0.9 0 24 56 80 104 8 16 32 40 48 64 72 88 96 ITT population Quetiapine (n=404) Placebo (n=404) Lithium (n=364) Time (weeks) Proportion of patients event free 1.0 0.0 0.6 0.8 0.2 0.4 0.5 0.7 0.1 0.3 0.9 0 24 56 80 104 8 16 32 40 48 64 72 88 96 ITT population QTP vs PLA HR 0.29 95% CI 0.23, 0.38 p-value <0.001 Prevencija rekurence u terapiji održavanja BAP (Kvetiapin XR) Weisler et al, 2008. Kvetiapin XR redukuje rizik rekurence za 74%
- 56. Poželjan profil antipsihotika u lečenju bipolarnog poremećaja Efektivno doziranje Brza i sveobuhvatna efikasnost Dobar profil bezbednosti • Jednostavno doziranje- jednom dnevno • Brzo dostizanje efektivne doze • Jasna ciljna doza • Stabilna koncentracija u plazmi • Dobar terapijski indeks • Doprinosi adherenci i boljem odnosu lekar – pacijent • Brza kontrola simptoma u akutnoj fazi (maniji/ depresiji/ mesovitoj) • Efikasnost u različitim subgrupama pacijenata: BAP I, II, Rapid Cycling • Prevencija relapsa u terapiji održavanja - eutimije • Podržava psiho- socijalnu integraciju • Dobra bezbednost i podnošljivost tokom dugotrajne terapije • Niska incidenca somnolencije i EPS než.efekata • Bez seksualne disfunkcije/ povećanja prolaktina • Manji efekat na povećanje težine/ metaboličke komplikacije Jedan lek koji efikasan u svim fazama BAP, bez izraženih neželjenih efekata
- 57. Kvetiapin XR je jedini atipični antipsihotik registrovan i u MDD, i u shizofreniji i kao monoterapija jednom dnevno u oba pola BAP Quetiapin XR je registrovan kao dodatna terapija za veliki depresivni poremećaj i u shizofreniji za prevenciju relapsa, za razliku od Kvetiapin IR-a Quetiapin XR je jedini atipični antipsihotik registrovan za dodatnu terapiju velikog depresivnog poremećaja u EU Schizo- phrenia Bipolar Mania Bipolar Depression Relapse Prevention in Bipolar Disorder MDD Adjunct Therapy Quetiapin XR Quetiapin - Olanzapine - * - Risperidone - - - Ziprazidon - * - Clozapine ** - - - - * Kod pacijenata sa manijom kao index epizodom **Terapo rezistentna shizofrenija 1http://www.medicines.org.uk/EMC/default.aspx, Atipični antipsihotici - registrovana indikacije (EU)1
- 58. Da li se atipični antipsihotici mogu smatrati stabilizatorima raspoloženja: 1. Da 2. Da, ali ne svi 3. Ne 4. Nisam siguran
- 59. QUETIAPIN XR Kao monoterapija ili u kombinaciji može se smatrati stabilizatorom raspoloženja u svakoj fazi BAP-a i terapiji održavanja - u dozi 300mg do 600mg- EUTIMIJA terapija održavanja MANIJA DEPRESIJA
Editor's Notes
- 22 million patients have received quetiapine. This offer a tremendous data base of information on relationship between efficacy, exposure and allow opportunities for translation research. Quetiapine is a multi-target agent! Since launch in 1997, the use of quetiapine has spanned a decade of usage and capture of clinical experience. This clinical experience has been valuable to guide testing a number of hypothesis on the utility of quetiapine across a number of psychiatric disorders, and offer back translation opportunities to understand what are the candidate targets important to the clinical action, AND rule of engagement when one think about such novel multi-target agent.
- This schematic depicts the various phases of bipolar disorder, from acute mania and depression events to the recurrence of mania following a period of remission. Patients typically alternate between periods of depression and/or mania and periods of normal or balanced mood. Mixed events, in which features of mania and depression occur simultaneously, may also present. Reference Vieta E, Goikolea JM. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord. 2005;7(suppl 4):21-33.
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- Bipolar disorder is a lifelong illness, usually necessitating lifelong treatment. Although the initial aim of any management approach is to stabilize the acutely ill patient, treatment does not stop once euthymia has been achieved and the subsequent goal of treatment is to prevent or delay the recurrence of subsequent mood events or episodes, while maintaining a good quality of life for the patient. Clearly, an agent that is effective across all phases of bipolar disorder—from stabilization to mood event prevention—and across various patient subgroups, could greatly simplify any management approach.
- The efficacy of quetiapine XR in bipolar mania was determined in a 3-week, double-blind, placebo-controlled study of 316 patients with bipolar I mania, randomized to treatment with quetiapine XR 400-800 mg or placebo once daily (Cutler, et al, 2008). Study completion rates were similar between quetiapine XR and placebo treatment groups (71.6% vs 72.0% for quetiapine XR and placebo, respectively). The mean dose of quetiapine XR was 603.8 [175.9] mg/d (mean [SD]). On the primary efficacy measure, the mean improvement in YMRS total score associated with quetiapine XR was significantly greater than that associated with placebo from Day 4 through study endpoint (-14.34 vs -10.52; LOCF; P<0.001). Quetiapine XR treatment was associated with significantly higher rates of YMRS response and remission at study endpoint (Week 3) compared with placebo (response 55.0% vs 33.3% [P<0.001]; remission 41.6% vs 27.7% [P=0.006]). Reference Cutler A et al. Poster presented at IRBD; April 2008; Copenhagen, Denmark.
- Combination therapy with quetiapine IR (up to 800 mg/d) + Li (0.7-1.0 mEq/L) /DVP (50-100 ug/mL) was compared with placebo+Li/DVP in 2 randomized, double-blind studies of 3 or 6 weeks’ duration (Study 99 [5077IL/099], N=191 and Study 100 [5077IL/0100], N=211). Study completion rates at Day 21 were 64.8% and 54.7% for quetiapine+Li/DVP and placebo+Li/DVP, respectively (pooled dataset, N=402; Yatham, et al, 2004). The mean daily dose of quetiapine among responders during the last week of treatment was 492 mg/d. As observed with quetiapine monotherapy, quetiapine+Li/DVP combination therapy was associated with rapid and sustained improvement in mania symptoms, as demonstrated by significant improvement in YMRS total score at Week 3 following treatment with quetiapine+Li/DVP (P<0.05; pooled dataset). Significantly more quetiapine+Li/DVP- than placebo+Li/DVP-treated patients met criteria for response and remission at Day 21 (response; 55.7% vs 41.6%; remission; 48.7% vs 33.0% (P<0.01 for both comparisons; pooled dataset). As mentioned previously, statistical separation from placebo on the primary outcome measure was not observed in Trial 100, although numerically greater reductions in Young Mania Rating Scale (YMRS) total score were observed following treatment with quetiapine+Li/DVP (Yatham, et al, 2007). References Sussman, et al. Eur Psychiatry 2005;20(suppl 1):S140-1. Yatham LN, Paulsson B, Mullen J, et al. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24:599-606. Yatham LN, Vieta E, Young AH, et al. A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania. Int Clin Psychopharmacol. 2007;22:212-20.
- This meta-analysis of 12 placebo-controlled monotherapy trials (published before 2004) demonstrates the superior effectiveness of the atypical antipsychotics over placebo in the treatment of mania, and shows their comparability with traditional treatments such as the mood stabilizer, lithium, and the conventional antipsychotic, haloperidol (Perlis, 2006). As illustrated in the figure, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole all show significant efficacy as monotherapy (as evidenced by the fact that all confidence intervals in the pooled analysis exclude zero). After adjusting for multiple comparisons of individual effects, there were no significant differences in efficacy between the atypical antipsychotics, suggesting a consistency of effect in mania. Reference Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry. 2006;67:509-16.
- Why should an antipsychotic be active in depressive orders? References: Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006 Dec;26(6):600-9. Erratum in: J Clin Psychopharmacol. 2007;27(1):51.
- For patients with bipolar depression, the therapeutic potential of any treatment option may be dramatically offset by its propensity to induce hypomania or mania. In bipolar depression studies, quetiapine was generally associated with low rates of switching to mania. In the BOLDER/EMBOLDEN pooled dataset, the incidence of treatment-emergent mania (defined as an adverse event classified as “mania”/“hypomania” and/or by a YMRS total score ≥16) was 3.0% in both quetiapine groups compared with 5.0% in the placebo group (Calabrese, et al, 2009). In Trial 002XR, the incidence of treatment-emergent mania was lower in the quetiapine XR 300 mg daily group than in the placebo group (4.4% vs 6.4%, respectively; Suppes, et al, 2008a). References Suppes T, Datto C, Minkwitz M, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2009 Nov 8. doi:10.1016/j.jad.2009.10.007. Calabrese JR, et al. Poster presented at the 162nd APA meeting; May 2009; San Francisco, California.
- Clinical studies conducted in bipolar depression to date, generally show a high rate of “failure” (or lack of separation from placebo on the primary efficacy endpoint), with quetiapine and olanzapine standing out as monotherapies with proven antidepressant efficacy. With 5 positive placebo-controlled trials, quetiapine has the most evidence for efficacy as monotherapy in bipolar depression. References Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-60. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26:600-9. Young AH, et al. Poster presented at 3rd Biennial ISBD Meeting; January 2008a; Delhi, India. McElroy S, et al. Poster presented at 3rd Biennial ISBD Meeting; January 2008; Delhi, India. Suppes T, et al. Poster presented at the 8th IRBD meeting; April 2008a; Copenhagen, Denmark. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003a;60:1079-88. Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10:323-33. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28:13-20. Sachs G, et al. Poster presented at ISCTM 5th Annual Meeting; March 2009; Arlington, USA.
- To date, a number of atypical antipsychotics have demonstrated long-term maintenance of efficacy in bipolar disorder (eg, aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone). Between-treatment differences derive from the nature of the index episode, the type of mood event prevented, and efficacy/tolerability profiles. References Keck PE Jr, Calabrese JR, McIntyre RS, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry. 2007;68:1480-91. McElroy S, et al. Poster presented at 3rd Biennial ISBD Meeting; January 2008; Delhi, India. Suppes T, Vieta E, Liu S, et al. Maintenance treatment for patients with bipolar I disorder: results from a north american study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry. 2009;166:476-88. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry. 2003;160:1263-71. Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163:247-56. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008;109:251-63. Vieta E, Nieto E, Autet A, et al. A long-term prospective study on the outcome of bipolar patients treated with long-acting injectable risperidone. World J Biol Psychiatry. 2008;9:219-24. Vieta E, et al. Poster presented at EPA; January 2009; Lisbon, Portugal. Weisler RW, et al. Poster presented at 60th IPS Congress; October 2008; Chicago, USA. Young AH, et al. Poster presented at 3rd Biennial ISBD Meeting; January 2008a; Delhi, India.
- Interim analysis (interim ITT population) The time to recurrence of any mood event in the interim ITT population was significantly longer in patients who continued quetiapine treatment compared with patients who switched to placebo. The risk for recurrence of any mood event for quetiapine vs placebo, expressed as HR, was 0.26 (P<0.001), corresponding to a risk reduction of 74% in favor of quetiapine. Based on the positive results of the interim analysis, the study was halted according to predefined criteria. Time to recurrence of any mood event (ITT population) Analysis of the ITT population supported the interim analysis by showing a significantly longer time to recurrence of any mood event in patients who continued quetiapine compared with those who switched to placebo (Figure). The risk for recurrence of any mood event was 0.29 (P<0.001) for quetiapine vs placebo, corresponding to a risk reduction of 71%. The risk for recurrence of any mood event was also significantly lower in patients who switched to lithium rather than placebo (HR, 0.46; P<0.0001) and was significantly lower in patients who continued quetiapine compared with those who switched to lithium (HR, 0.66; P=0.005). Reference Weisler RW, et al. Poster presented at 60th IPS Congress; October 2008;Chicago,USA.
- Bipolar disorder is a lifelong illness, usually necessitating lifelong treatment. Although the initial aim of any management approach is to stabilize the acutely ill patient, treatment does not stop once euthymia has been achieved and the subsequent goal of treatment is to prevent or delay the recurrence of subsequent mood events or episodes, while maintaining a good quality of life for the patient. Clearly, an agent that is effective across all phases of bipolar disorder—from stabilization to mood event prevention—and across various patient subgroups, could greatly simplify any management approach.