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” Effectiveness of long-acting antipsychotics in the treatment of schizophrenia ”

” Effectiveness of long-acting antipsychotics in the treatment of schizophrenia ”. José M. Olivares Department of Psychiatry. EOXI Vigo Instituto Biomédico Galicia Sur Vigo (Spain). Disclosures. Have been involved in advisory boards of Eli Lilly, Janssen-Cilag and AstraZeneca

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” Effectiveness of long-acting antipsychotics in the treatment of schizophrenia ”

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  1. ”Effectiveness of long-acting antipsychotics in the treatment of schizophrenia” José M. Olivares Department of Psychiatry. EOXI Vigo Instituto Biomédico Galicia Sur Vigo (Spain)

  2. Disclosures Have been involved in advisory boards of Eli Lilly, Janssen-Cilag and AstraZeneca Have been the recipient of compensation from Janssen-Cilag, Lundbeck, Otsuka, AstraZeneca, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis and Pfizer.

  3. J Clin Psychiatry 2001; 62(1): 6-7.

  4. Results of efficacy studies (RCT) seem confusing due to: • Biased samples (selected patients) • Inclusion and exclusion criteria. • Low and/or fixed doses • Statistics and Methodologies. • Sponsoring by pharmaceutical companies Heres, Davis, Maino, et al. Am J Psychiatry 163:2, February 2006

  5. Populations in RCT are highly selected • 420 SCH patients consecutively admitted who fulfilled usual RCT inclusion and exclusion criteria Reproduced with permission of Dr Enric Álvarez. Departmento de Psiquiatría, Hospital Santa Creu i Sant Pau, Barcelona.

  6. Tolerability and security Efficacy Effectiveness Adherence What is Effectiveness?Treatment perspective TIME TO DISCONTINUATION: Good variable to assess effectiveness Lehman AF, et al. Am J Psychiatry. 2004;161(2 suppl):1-56. Swartz MS, et al. Schizophr Bull. 2003;29(1):33-43. Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.

  7. What is Effectiveness?Clinicians’ perspective • Clinicians prefer outcome measures: • With clinical significance • With the goal of maximazing generalizability • That address practical questions about risks, benefits and costs in routine clinical practice. • Quality of life and Social Functioning: good constructs to assess Effectiveness Kwon JS & Jung-Seok Ch. World Psychiatry. 2009 Feb; 8(1): 35–36.

  8. High rates of acute response* to treatment in first episode schizophrenia *Response: ”Much” or ”very much” improved on CGI Mild or less on SADS psychosis items Maintained for 8 consecutive weeks n=118 CGI, Clinical Global Impression SADS, Schedule for AffectiveDisorders and Schizophrenia Dotted lines represent 95% confidence intervals for percent of patients responding Robinson D.G. et al. Am J Psychiatry 1999;156:544-549

  9. What are the real outcomes? • Treatment response is better in first episode than in multi-episode patients1 • 7-year follow-up study:2 • 80% deteriorated • Degree of deterioration significantly correlated with the number of relapses • 15-year follow-up study:3 • Striking finding: one in six patients did not remit after each episode • More time to response:4 • Increased times to treatment response in succeeding episodes 1. Robinson et al. Arch Gen Psychiatry 1999;56:241–247; 2. Curson et al. Br J Psychiatry 1985;146:474–480; 3. Wiersma et al. Schizophr Bull 1998;24:75–85; 4. Lieberman et al. Neuropsychopharmacology 1996;14(suppl 3):13S–21S

  10. First episode patients are at high risk of relapse 100 Relapse rate (95% CI) 82% 90 78% 80 70 54% 60 50 40 30 n=104 n=104 n=63 20 10 0 Risk of 1st relapse over 24 months Risk of 1st relapse over 5 years Risk of 2nd relapse over 5 years There is a high rate of relapse within 5 years after a first episode Robinson et al. Arch Gen Psychiatry 1999;56:241–247

  11. Illness progression after relapse • A 15-year follow-up study examined the natural course of schizophrenia after each of the first four psychotic episodes (82 patients) Patients with persistence of positive and/or negative symptoms Mean duration of subsequent psychotic episodes* *First episode mean duration=20 months Emsley et al. Schizophr Res 2013;148(1–3):117–121; Wiersma et al. Schizophr Bull 1998;24(1):75–85

  12. Illness progression after relapse Increased time to treatment response in successive episodes • 70 patients with first-episode schizophrenia were treated according to a specific protocol and followed-up over 5 years • If patients relapsed they were placed back onto their original treatment Time to remission in patients who had two episodes (n=22) Time to remission in patients who had three episodes (n=6) p=0.001 p=0.06 Emsley et al. Schizophr Res 2013;148(1–3):117–121; Lieberman et al. Neuropsychopharmacology 1996;14(3 Suppl):13S–21S

  13. Grey matter decrease and the number of hospitalizations in schizophrenia patients 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 n=92 p=0.03 van Haren et al. Neuropsychopharmacology 2007;32:2057–2066

  14. Relapse duration and brain tissue loss in schizophrenia: A prospective longitudinal MRI study Plot of Duration of Relapse By Interscan Interval in a Longitudinal Study of 202 Schizophrenia Patientsa • 202 patients with first-episode schizophrenia • MRI data (N=659 scans) over an average of 7 years • Relapse duration was related to significant decreases in both general (e.g.,total cerebral volume) and regional (e.g.,frontal) brain measures) aScatterplot depicts the pattern of symptomatic relapse in schizophrenia patients during the longitudinal follow-up period. Duration of relapse is plotted against each interscan interval (years). Early phases of the illness are characterized by multiple relapses of shorter durations. Andreasen et al. Am J Psychiatry 2013 Apr 5. [Epub ahead of print]

  15. Animal (rat) model for the progressive pathophysiology of schizophrenia – haloperidol induces apoptosis • Repeated administration of methamphetamine (METH) increases extracellular glutamate in the mPFC • Induces apoptosis (TUNEL-positive cells) • Repeated administration of aripiprazole (3.0 mg/kg) or haloperidol (0.1 mg/kg) with METH markedly attenuates the induction of apoptosis • Neuroprotective effect • However, repeated administration of haloperidolwithout METH induces apoptosis • Neurotoxic effect Extent of apoptosis Mean Single animal (left or right side) Concentration of TUNEL-positive cells in the mPFC (cells/mm2) Vehicle + saline Vehicle + METH Haloperidol + saline Aripiprazole + saline Haloperidol + METH Aripiprazole + METH Abekawa et al. Schizophr Res 2011;125(1):77–87 #p<0.01 vs. vehicle + saline; *p<0.01 vs. vehicle + METH; mPFC=medial prefrontal cortex

  16. Implications of relapse 1. Emsley et al. Schizophr Res 2013;148(1–3):117–121; 2. Kane. J Clin Psychiatry 2007;68(Suppl 14):27–30; 3. Ascher-Svanum et al. BMC Psychiatry 2010;10:2

  17. Preventing relapse in schizophrenia • Preventing relapse is a key goal highlighted in many international clinical guidelines1–3 • Medication discontinuation is one of the top predictors of relapse in schizophrenia4 • Treatment discontinuation increases the relapserisk five-fold4 • The chance of relapse is decreased if pharmacotherapycontinues uninterrupted5 • Other risk factors include:3 • Substance abuse, residual symptoms, poor insight Relapse prevention strategies should ensure periods of non-adherence to medication are minimized3 1. NICE Schizophrenia Guidelines CG82, March 2009; 2. APA Practice Guidelines, 2004. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2ePG_05-15-06; 3. Barnes et al. J Psychopharmacol. 2011 Feb 3 [Epub ahead of print]; 4. Robinson et al. Arch Gen Psychiatry 1999;56:241–247; 5. Kane. J Clin Psychiatry 2007;68(suppl 14):27–30

  18. Relapse after antipsychotic discontinuation in remitted subjects after 24-month treatment Survival functionComplete Censored 1.2 1.1 94% relapse rate Median time to relapse = 15 wks 1.0 0.9 0.8 0.7 Cumulative proportion surviving 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 70 80 n=33 Survival time (weeks) Patients with recent onset psychosis who achieved remission relapsed after stopping treatment with RLAI, therefore, treatment continuation should be considered RLAI, risperidone long-acting injectable Emsley et al. Eur Neuropsychopharmacol 2009;19(suppl 3):S486

  19. Relapse cannot be predicted Mean PANNS score 100 90 80 70 60 Total PANSS score 50 40 30 20 10 0 8 7 6 5 4 3 2 1 0 Months before relapse n=26 PANSS, Positive and Negative Syndrome Scale Emsley et al. Eur Neuropsychopharmacol 2009;19(suppl 3):S486

  20. Why is adherence still a challenge in patient care? • Non-adherence is more common than treatment refusal or discontinuation • Medications with improved safety and tolerability profiles have not improved adherence rates • HCPs focus on difficult-to-treat patients on maintenance therapy • Patients who openly refuse or repeatedly discontinue treatment HCP, healthcare practitioner Masand et al. Prim Care Companion J Clin Psychiatry 2009;11:147–154

  21. Rates of non-adherence to treatment in schizophrenia are high • In study of 34,128 patients, 61% had adherence difficulties† at some point over 4-year period following initial diagnosis1 • ~18% had consistently poor adherence • 43% were inconsistently adherent • 39% had consistently good adherence †Determined using medication possession ratio • Valenstein et al. J Clin Psychiatry 2006;67:1542–1550

  22. Antipsychotic discontinuation after a first hospitalization for schizophrenia • Nationwide cohort study conducted 2000–2007 in Finland (n=2588) Collected a prescription during the first 30 days after discharge Continued their initial treatment for 30 days or longer Tiihonen et al. Am J Psychiatry 2011;168:603–609

  23. Comparison of Atypicals in First-Episode psychosis (CAFE): randomized 52-week trial All-cause treatment discontinuation All-cause Patient decision Side effects Inadequatetherapeutic effect Olanzapine Quetiapine Risperidone Administrative 0 20 40 60 80 Discontinuation (%) Broad inclusion and minimal exclusion criteria used to enrol patients similar to those seeking treatment in clinical practice • n=400 McEvoy et al. Am J Psychiatry 2007;164:1050–1060

  24. Adherence challenges affect almost all patients* Mean number of days with ‘no therapy’ Continuous therapy ANY ‘no therapy’ days † 5.2% 7.1% 100 350 94.8% 92.9% 300 80 250 60 Patients (%) 200 Days 125.0 40 150 110.2 100 20 50 0 0 SGA FGA FGA SGA n=349 n=326 n=349 n=326 *Based on availability of medication in a 1-year naturalistic study †’No therapy’ defined as days in which medication was not available. Patients were considered to be receiving therapy on days when medication was available and COULD have been taken Mahmoud et al. Clin Drug Invest 2004;24:275–286

  25. Partial Adherence and Nonadherence Led to Increased Hospitalization Time spent hospitalized Rate of hospitalization * * * * Rate, % Time, days Adherent was defined as an MPR ≥80%, partially adherent was defined as an MPR ≥60% and <80%, and nonadherent was defined as an MPR <60%. * P<0.05 vs adherent.MPR=medication possession ratio. Ascher-Svanum H et al. BMC Res Notes. 2009;2:6.

  26. p<0.001 4 Risk of hospitalization p<0.001 3 p=0.0042 2 1 n=327 n=1710 n=1166 n=1122 0 0 days 1–10 days 11–30 days 30+ days Missed therapy over 1 year Even 1–10 days therapy missed per year leads to an increased risk of hospitalization Californian Medicaid assessment (n>4000 patients) p values given with 0 days as the referent Weiden et al. Psychiatric Services 2004;55:886–891

  27. Real-World Studies Favour Use of LAIsRCT studies: good adherent samples? As study design shifts toward real-world populations, LAI formulations display significant advantages 2.2 2.0 Relapse Favors oral 1.8 Hospitalization 1.6 All-cause discontinuation 1.4 Overall 1.2 Adjusted Risk Ratio 1.0 0.8 FavorsLAI 0.6 RR=0.877 0.4 RR=0.622 RR=0.558 0.2 0 Randomized Clinical Studies ProspectiveStudies RetrospectiveStudies RCT Real-world LAI=long-acting injectable; RCT=randomized controlled trial; RR=risk ratio. Kirson N et al. Presented at: 52nd Annual Meeting of New Research Approaches for Mental Health Interventions; May 29-June 1, 2012; Phoenix, AZ.

  28. LAIs reduce the risk of hospitalisation in Finland Treatment HR p value Cohort study of patients followed between 2000 and 2007 (n=2588) Haloperidol LAI 0.21 0.13 Clozapine 0.48 0.001 Olanzapine 0.54 <0.0001 Other antipsychotics 0.56 0.09 Risperidone LAI 0.57 0.09 Perphenazine LAI 0.59 0.11 Polypharmacy 0.92 0.62 Zuclopenthixol LAI 0.95 0.92 Risperidone oral 1.00 0.76 Perphenazine oral 1.11 0.60 Quetiapine 1.11 <0.0001 No treatment 1.63 0.28 Haloperidol oral 1.79 Zuclopenthixol oral 1.93 0.29 4 pooled LAI vs oral mother compounds 0.36 0.007 Favours LAI Favours oral antipsychotics Adjusted HR (95% CI) CI, confidence interval; HR, hazard ratio; LAI, long-acting injectable Tiihonen J et al. Am J Psychiatry 2011;168:603-9

  29. Depot formulations vs. oral APS: an old story • 100 • Fluphenazine decanoate (n=55) • Fluphenazine oral (n=50) • 90 • 80 • 70 • Proportion of patients • without relapse (%) • 60 • 50 • 40 • 30 • 0 • 6 • 12 • 18 • 24 • Months in community Hogarty et al. Arch Gen Psychiatry 1979;36:1283–1294; Kane. J Clin Psych 2006;67(suppl 5):9–14

  30. LAI Antipsychotics Increase Time to Medication Discontinuation Compared to Oral Antipsychotics Time to discontinuation for any reason with typical antipsychotics* in the first year after medication initiation 1.0 LAI (n=97) 0.9 Oral (n=202) Time to Discontinuation for Any Reason With TypicalAntipsychotics* in the First Year After Medication Initiation 0.8 0.7 0.6 Proportion P<0.01 0.5 0.4 0.3 0.2 0.1 0 Days 0 50 100 150 200 250 300 350 In a 3-year observational study, patients with schizophrenia treated with LAI antipsychotics demonstrated a significantly longer time to discontinuation Data from the US Schizophrenia Care and Assessment Program, a large, prospective study of treatment for schizophrenia, schizoaffective disorder, or schizophreniform disorders conducted July 1997 through September 2003 (n=2327). * Includes fluphenazine and haloperidol. LAI=long-acting injectable. Zhu B et al. Psychiatr Serv. 2008:59(3):315-317.

  31. Discontinuation rates on oral versus Risperidone LAI: 24-month report from Spain (e-STAR) 100 95 90 86.1% 85 81.8% 80 76.7% % patients remaining on treatment 75 70 63.4% 65 60 RLAI patients (n=1345) Oral patients (n=277) 55 50 0 90 180 270 380 450 540 630 720 Time on treatment (days) Olivares JM et al. European Psychiatry (2009)

  32. Paliperidone palmitate vs. oral APS By the end of the 24-month treatment phase, 52 (14.8%) patients met relapse criteria in the PP group versus 76 (20.9%) patients in the oral AP group (p=0.0323) This represents a 29.4% relative risk reduction in favour of PP 1.0 Kaplan–Meier plot of time to relapse Core ITT for efficacy population 0.9 Proportion of patients not relapsing 0.8 Paliperidone palmitate (n=352) Any oral AP (n=363) 0.7 0 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Days *According to Csernansky criteria †log-rank test AP, antipsychotic; HR, hazard ratio; TT, intent-to-treat; PP, paliperidone palmitate; • Time to relapse* was significantly longer in the PP group compared to the oral AP group (p=0.0191,HR [95% CI] 1.5 [1.1; 2.2])† • The 85th percentile for time to relapse was 469 days in the PP group vs 249 days in the oral AP group2 Schreiner A et al. Poster presented at CINP, 22–26 June 2014, Vancouver, Canada, Poster LP-01-013)

  33. Aripiprazol once monthly vs oral Time to all-cause discontinuation 1.0 0.8 * 0.6 Proportion of patients free of event ** 0.4 Aripiprazole once monthly 400 mg Oral aripiprazole 10–30 mg/day Aripiprazole once monthly 50 mg 0.2 0 0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 224 238 252 266 Days from randomisation Log-rank test: * Aripiprazole once monthly 400 mg vs. oral aripiprazole 10–30 mg/day; p=0.0484 ** Aripiprazole once monthly 400 mg vs. aripiprazole once monthly 50 mg; p<0.0001 a Patients discontinued prior to or on Day 280 in Phase 3; ITT sample Fleischhacker WW, et al. Br J Psychiatry. 2014 [Epub ahead of print].

  34. Kane JM et al. J Med Econ. 2014; doi: 10.3111/13696998.2014.979936 Hospitalization Rates in patients switched from Oral Antipsychotics to Aripiprazole Once-Monthly: a Mirror Study

  35. Study Design Retrospective oral SOC treatment Prospective aripiprazole once-monthly treatment Start Phase B (n=433) (1st dose) Patient signs informed consent 4thdose Month-7 Month-4 Month-1 Month0 Month3 Month6 Extension Phase Screening and Oral Conversion Phase A(1-4 weeks) 3-month hospitalization data (n=336) 3-month hospitalization data (n=336) 6-month hospitalization data (n=433) 6-month hospitalization data (n=433) Pre-specified 1-month period that patient must be stable and an outpatient SOC: standard-of-care. Kane JM et al. J Med Econ. 2014; doi: 10.3111/13696998.2014.979936.

  36. Total psychiatric hospitalization rates before and after prospective treatment with aripiprazole once-monthly Total psychiatric hospitalization rate between retrospective period (Months –4 to –1) and prospective period (Months 4 to 6) p<0.0001 Total psychiatric hospitalization rate between retrospective 6-month period and prospective 6-month period p<0.0001 Percentage of patients with ≥1psychiatric hospitalization Patients who completed 3 months treatment on aripiprazole once-monthly (n=336) All patients who entered Phase B treatment with aripiprazoleonce-monthly (n=433) Kane JM et al. J Med Econ. 2014; doi: 10.3111/13696998.2014.979936.

  37. Aripiprazole once-monthly vs. paliperidone palmitate in a randomized, head-to-head clinical study Naber D, et al. Presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria

  38. Methods • Phase 3b, multicenter, 28-week, randomized, open-label, rater-blinded, parallel group study (NCT01795547) • Direct comparison of the treatment effectiveness of two atypical LAIs: AOM 400 and PP • AOM 400: 400mg maintenance dose with reduction to 300mg permitted based on the individual patient tolerability • PP: flexible dosing of 50 to 150 mg/month (EU and Canada) or equivalent 78 to 234 mg/month (US). • Primary outcome: Heinrichs-Carpenter Quality-of-Life Scale (QLS) • Key secondary outcome: Clinical Global Impression – Severity scale (CGI-S) Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria

  39. Study design Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria

  40. ResultsPatient disposition and exposure • The treated patient population (n=281) was stable at baseline • 100/148 (67.6%) in the AOM 400 and 83/147 (56.5%) in the PP group completed 28 weeks of treatment. • The mean doses (±SE) at week 24 were 387.0±3.4 mg for AOM 400 and 110.3±3.6 mg (EU and Canada) for PP, equivalent to a mean of 172 mg (US). Doses were in line with recommended monthly maintenance doses of AOM 400 and PP. Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria

  41. Results Significant improvements with AOM 400 compared to PP treatment on Heinrichs-Carpenter Quality-of-Life Scale (QLS) total scores * * * Weeks Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria Least square mean [LSM] changes from baseline are analyzed with a mixed model for repeated measures, and *p<0.05 indicates significant differences between treatments (AOM 400 vs PP). Error bars indicate standard error of the LSM

  42. Results Significant improvements with AOM 400 compared to PP treatment on Clinical Global Impression – Severity scale (CGI-S) scores. Weeks ** * * * ** ** Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria Least square mean [LSM] changes from baseline are analyzed with a mixed model for repeated measures, and *p<0.05, **p<0.01 indicate significant differences between treatments (AOM 400 vs PP). Error bars indicate standard error of the LSM.

  43. Results Treatment-emergent adverse events (TEAEs) occurring in ≥5% frequency in any group of any phase Naber D, et al. Poster presented at the 23rd European Congress of Psychiatry (EPA); March 28-31, 2015, Vienna, Austria

  44. Conclusions • Results of efficacy studies are difficult to generalize to routine clinical practice. • Effectiveness may be defined in different ways • Efficacy and tolerability are not enough: adherence has important implications for patient outcome, from the outset of the disease • The majority of schizophrenia patients are partially or non-adherent • Continuous pharmacological treatment combined with psychosocial treatments improve the possibility of achieving functional recovery and getting a good quality of life. • LAIs play a key role in the treatment of schizophrenia, particularly within the first years after diagnosis. • More effectiveness studies are needed, particularly head-to-head studies

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