Faculty Disclosure. Strategies to Improve Treatment Adherence in Schizophrenia: A Focus on Long-Acting Injectable Antipsychotics

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1 Strategies to Improve Treatment Adherence in Schizophrenia: A Focus on Long-Acting Injectable Antipsychotics Presented by: Richard Jackson, MD Associate Clinical Professor of Psychiatry Wayne State University School of Medicine Department of Psychiatry Detroit, Michigan Assistant Clinical Adjunct Professor of Psychiatry University of Michigan School of Medicine Department of Psychiatry Detroit, Michigan Authored by: John M. Kane, MD Chairman and Professor of Psychiatry, Hofstra Northwell School of Medicine Hempstead, New York Chairman, Department of Psychiatry, The Zucker Hillside Hospital Glen Oaks, New York Senior Vice President, Behavioral Health Services, Northwell Health Queens, New York Faculty Disclosure Dr. Jackson: Consultant Alkermes, Sunovion; Clinical Research Lundbeck, Neos, Neurocrine, Otsuka Pharmaceuticals, Takeda, Teva; Speakers Bureau Alkermes, Sunovion Dr. Kane: Consultant or Received Honoraria Alkermes, Allergan, Eli Lilly, Forum, Genentech, Lundbeck, Intracellular Therapies, Janssen, Johnson & Johnson, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda, Teva; Grant Support Otsuka, Janssen; Stock/Shareholder MedAvante, Inc., Vanguard Research Group, LB Pharmaceuticals, Inc.

2 Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing offlabel or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance. Learning Objectives Apply routine assessment strategies to identify and monitor adherence to antipsychotic therapy Explain the latest clinical data on long-acting injectable (LAI) antipsychotics, including safety, efficacy, tolerance, and implications on adherence Translate to practice the latest evidence with respect to treatment selection and identification of patient populations that would most benefit from LAIs Implement a shared-decision making approach to management that addresses patient preferences, concerns, and unique needs Overview Assessment and Monitoring of Adherence LAIs: Efficacy and Safety LAIs: Patient Selection Shared Decision Making Summary and Recommendations

3 A Basic Fact Difficulty with adhering to chronic medical treatments is a human characteristic It isn t just people with psychosis, it is most people Despite your excellent relationships with your patients, your patients are human so they have adherence problems like everyone else Help should be the norm, not just given to select people Non-adherence in the Treatment of Chronic Disorders In developed countries, about 5% of patients with chronic diseases adhere to long-term therapy 33% to 69% of all medication-related hospital admissions in the United States are due to poor medication adherence One-third of all prescriptions are never filled > 5% of filled prescriptions are associated with incorrect administration (not taken as prescribed) World Health Organization. Adherence to Long-term Therapies: Evidence for Action Accessed February 21, 217. Osterberg L, et al. N Engl J Med. 25;353(5): Peterson AM, et al. Am J Health Syst Pharm. 23;6(7): Antipsychotic Non-adherence in Adult Outpatients with Schizophrenia Point Prevalence Study Non-adherence Measure Baloush-Kleinman V, et al. Schizophr Res. 211;13(3): % Patients/relatives Huang WF, et al. Journal of Food and Drug Analysis. 29;17(6): % Patient report Jónsdóttir H, et al. Acta Psychiatr Scand. 213;127(2): % Patient report Klingberg S, et al. Psychiatry Res. 28;161(2): % Clinician ratings McCabe R, et al. PLoS One. 212;7(4):e % Clinician ratings Meier J, et al. Epidemiol Psichiatr Soc. 21;19(3): % Clinician ratings Rabinovitch M, et al. Can J Psychiatry. 29;54(1): % Clinician ratings

4 Poor Antipsychotic Adherence over Time in Schizophrenia 7 6 Adherence (%) Year 1 Year 2 Year 3 Year 4 Any Year Analysis of 34,128 VA patients with schizophrenia receiving regular outpatient mental healthcare. Poor antipsychotic adherence defined as annual MPR <.8. 18% had poor antipsychotic adherence in all 4 years. MPR = medication possession ratio; VA = Veterans Affairs. Valenstein M, et al. J Clin Psychiatry. 26;67(1): Detection of Antipsychotic Non-adherence Detected (%) Self-report Physician Pill Count Criterion standard (n = 19) is MEMS MPR.8 over 12 weeks, compared with patient self-report, physician impressions, and unannounced in home pill counts. Patient and physician reports correlated with BPRS. BPRS = Brief Psychiatric Rating Scale; MEMS = Medication Event Monitoring System. Velligan DI, et al. Psychiatr Serv. 27(9): Potential Clinical Consequences of Undetected Medication Non-adherence Unidentified non-adherence may lead to unnecessary Antipsychotic medication changes Dosage increases Concomitant antipsychotic medications Labeling of patients as treatment resistant Identify patient adherence patterns then find the best treatment option Velligan DI, et al. Psychiatr Serv. 27(9): Velligan DI, et al. Schizophr Bull. 26;32(4): Byerly M, et al. Psychiatry Res. 25;133(2-3):

5 Base Characteristics of Selected First- and Second-Generation LAIs: United States Fluphenazine decanoate Dose Interval (weeks) Dosage Forms/ Strengths Oil Varies 25 and 1 mg/ ml ampoules/ vials/syringes Starting Dose Varies, 12.5 mg Maintenance Dose Varies, mg Oral Supplementation Time to Peak Steady State Post-injection Observation No 2 4 days 2 3 months No Haloperidol decanoate Oil 4 5 and 1 mg/ ml ampoules Varies, 5 mg Varies, 3 mg No 6 7 days 2 3 months No Risperidone LAI Water 2 25, 37.5, 5 mg vial kits 25 mg 25 mg (25 5 mg) 3 weeks 4 6 weeks months No Olanzapine pamoate Paliperidone palmitate Water 2 or 4 21, 3, 45 mg vial kits Water Monthly 78 mg 117 mg 156 mg 234 mg pre-filled syringes Varies, up to 3 mg/2 weeks 15 mg (Day 1) + 1 mg (Day 8) Varies, up to 3 mg/2 weeks 75 mg (25 15 mg) No 4 days 3 months At least 3 hours No 13 days 7 11 months No Paliperidone palmitate 3 month formulation Water 3-Monthly 273 mg 41 mg 546 mg 819 mg pre-filled syringes Depending on 1- monthly dose 75 mg (25 15 mg) No 3 33 days Continues steady state at equivalent dose No Aripiprazole LAI Water Monthly 3, 4 mg vial kits and dual Aripiprazole lauroxil chamber syringe Water Monthly 441 mg 662 mg 882 mg pre-filled syringes 4 mg 4 mg (3 4 mg) Varies, 441 mg, 662 mg, 882 mg 2 weeks 5 7 days 4: 4 8 months 3: 3 4 months No 21 days 5 6 days 4 months No Package inserts of each antipsychotic. Citrome L. Expert Rev Neurother. 213;13(7): Most Common Adverse Effects with SGA-LAIs RLAI PLAI OLAI ALAI The most common adverse reactions in clinical trials in patients with schizophrenia ( 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremities and dry mouth. The most common adverse reactions in clinical trials in patients with bipolar disorder were weight increase (5% in monotherapy trial), and tremor and parkinsonism ( 1% in adjunctive therapy trial). The most common adverse reactions (incidence 5% and occurring at least twice as often as placebo) were injection-site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. The most common adverse reactions ( 5% in at least 1 of the treatment groups and greater than placebo) associated with OLAI treatment included: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting. The most common treatment-emergent adverse reactions (occurring in 5% of ALAI patients and greater than placebo) were insomnia (1. vs 9.%), tremor (5.9 vs 1.5%), and headache (5.9 vs 5.2%). Akathisia occurred in 6.3% of patients receiving ALAI in the stabilization phase and 5.6% of ALAI patients in the double-blind treatment phase (vs 6.% for placebo-treated patients). ALAI = aripiprazole long-acting injection; OLAI = olanzapine pamoate long-acting injection; PLAI = paliperidone palmitate long-acting injection; RLAI = risperidone long-acting injection; SGA = secondgeneration antipsychotic. Citrome L. Expert Rev Neurother. 213;13(7): LAI Antipsychotics vs Placebo

6 13-Week Acute RCT Paliperidone Palmitate: PANSS Total Scores Efficacy with the First Dose Least-Squares Mean Change from Baseline Initiation Dose of 15 mg on Day 1 in deltoid muscle * * * * * End Point Day Placebo (n = 16) PP 25 mg (n = 155) PP 1 mg (n = 161) PP 15 mg (n = 16) *PP vs Placebo: All unadjusted P-values <.5 as early as Day 8 for 25 and 15 mg groups, and as early as Day 22 for 1 mg eq. PANSS = Positive and Negative Syndrome Scale; PP = paliperidone palmitate; RCT = randomized controlled trial. Pandina GJ, et al. J Clin Psychopharmacol 21;3(3): Aripiprazole Once-Monthly vs Placebo in Acute Schizophrenia: Primary Endpoint PANSS Total LS Mean Change from Baseline in PANSS Total Score Treatment Week * Placebo * Aripiprazole-OM 4 mg P <.1; *P <.1. Based on MMRM; mean baseline PANSS score: ARI-OM 4 mg (n = 162), 12.4; PBO (n = 167), Week persistence: ARI-OM: 64.3%; PBO: 49.4%. Discontinuation due to inefficacy: ARI-OM: 7.1%, PBO: 29.1%. Discontinuation due to intolerability: ARI-OM: 4.2%, PBO: 7.6. ARI = aripiprazole; LS = least squares; MMRM = mixed-model repeated measures; OM = oncemonthly; PBO = placebo. Kane JM, et al. J Clin Psychiatry. 214;75(11): * * * * Aripiprazole Lauroxil vs Placebo in Acute Schizophrenia: PANSS Total Change PANSS Total Score Mean Change from Baseline Treatment Day * Placebo (n = 196) Aripiprazole lauroxil 441 mg (n = 196) Aripiprazole lauroxil 882 mg (n = 24) P values are for aripiprazole lauroxil 441-mg and aripiprazole lauorxil 882-mg dose group vs placebo. *P =.4; P <.1. Meltzer HY, et al. J Clin Psychiatry. 215;76(8):

7 Prevention of Relapse with Selected LAI Antipsychotics vs Placebo (vs 45 mg/4 weeks olanzapine pamoate) 1 Number Needed to Treat Paliperidone palmitate LAI flexibly dosed mg/4 weeks Olanzapine pamoate LAI 15 mg/2 weeks Olanzapine pamoate LAI 3 mg/2 weeks Treatment and Dosage Olanzapine pamoate LAI 45 mg/4 weeks Aripiprazole-OM 4 mg/4 weeks Citrome L. Expert Rev Neurother. 213;13(7): Paliperidone Palmitate 3-Monthly vs Placebo Estimated Proportion of Patients without Relapse Month formulation of paliperidone palmitate (n = 16) Placebo (n = 145) Censored P <.1 Day Time Since Randomization (days) Time (days) No. of Patients Left: 3-mo Formulation: Placebo: Berwaerts J, et al. JAMA Psychiatry. 215;72(8): LAI Antipsychotics vs Oral Antipsychotics

8 No Differences in Study-Defined Relapse/All-Cause Discontinuation between LAIs and Oral Antipsychotics N studies Total RR P-value Fluphenazine Haloperidol Relapse Olanzapine LAI Risperidone LAI Zuclopenthixol Total All-Cause Discontinuation Fluphenazine Haloperidol Olanzapine LAI Risperidone LAI Zuclopenthixol Total Favors LAI Risk ratio (95% CI) Favors Oral APs No difference in adherence between pooled LAIs and oral APs (measured in 1 studies) 21 studies, n = AP = antipsychotic; CI = confidence interval; RR = relative risk. Kishimoto T, et al. Schizophr Bull. 214;4(1): LAI Antipsychotics Not Different Regarding Adverse Event Dropout Rate in Long-Term Studies Depot Oral Weight Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total % M-H, Random, 95% CI M-H, Random, 95% CI Arango Not estimable Barnes (.6, 13.23) Del Guidice Not estimable Falloon Not estimable Gaebel (.32, 2.) Hogarty (.57, 176.7) Potapov (.23, 4.37) Rifkin (1.14, 2.72) Schooler (.44, 2.39) Total (95% CI) (.7, 2.58) Total events Favors Depot Favors Oral Heterogeneity: Tau 2 =.17; Chi 2 = 6.84, df = 5 (P =.23); i 2 = 27%. Test for overall effect: Z =.88 (P =.38). M-H = Mantel-Haenszel. Leucht C, et al. Schizophr Res. 211;127(1-3): PROSIPAL: Time to Relapse Proportion of Patients Not Relapsing Paliperidone palmitate (n = 352) Any oral AP (n = 363) Kaplan Meier plot of time to relapse Core ITT for efficacy population Days Patients in the treatment phase PP Oral AP By the end of the 24- month treatment phase, 52 (14.8%) patients met relapse criteria in the PP group vs 76 (2.9%) patients in the oral AP group (P =.323). This represents a 29.4% RR reduction in favor of PP. Time to relapse* was significantly longer in the PP group compared to the oral AP group (P =.191, 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 group *According to Csernansky criteria log-rank test. HR = hazard ratio; ITT = intent-to-treat; PROSIPAL = Prevention of Relapse with Oral Antipsychotics versus Injectable Paliperidone Palmitate study. Schreiner A, et al. Schizophr Res. 215;169(3):

9 Paliperidone Palmitate vs Oral Antipsychotics in Schizophrenia Patients with History of Incarceration and Substance Abuse Kaplan-Meier Curves of (A) Estimated Time to First Treatment Failure and (B) Estimated Time to First Psychiatric Hospitalization or Arrest/Incarceration for PP vs Oral Antipsychotics A 1. + Censored Oral Antipsychotic (n = 218) PP (n = 226) B 1. Estimated Proportion of Participants without Event Log-Rank P Value:.11 HR (Oral Antipsychotic vs PP): % CI of HR: (1.9, 1.88) Log-Rank P Value:.19 HR (Oral Antipsychotic vs PP): % CI of HR: (1.6, 1.93) Days since Random Assignment No. of Participants at Risk: Days since Random Assignment Oral PP Alphs L, et al. J Clin Psychiatry. 215;76(5): % vs 5% Relapse in 86 First-Episode Schizophrenia Patients Randomized to Oral Risperidone vs Risperidone LAI.5 Proportion Relapsed Oral risperidone group Long-acting injectable risperidone group Time Study (days) 365 Excellent levels of adherence: RLAI = 95% vs Oral Risperidone = 33%. Subotnik KL, et al. JAMA Psychiatry. 215;72(8): In Mirror Image Studies, LAIs Reduce Risk of Hospitalization Compared with Oral Antipsychotics Study RR P-value Girardi et al., LAIs showed strong superiority over oral Beauclair et al., <.1 APs in preventing Arato & Erdos, <.1 hospitalization Devito et al., <.1 Denham & Adamson, <.1 Morritt, <.1 Lam et al., <.1 Lindholm, <.1 Peng et al., <.1 Gottfries & Green, Rosa et al., Chang et al., <.1 Johnson & Freeman, <.1 Crivera et al., <.1 Ren et al., <.1 Svestka et al., Total (16 studies) (n = 466).43 <.1 Favors LAI Favors Oral APs Kishimoto T, et al. J Clin Psychiatry. 213;74(1):

10 Fewer Hospitalizations and Bed Days When Switching from RLAI to PLAI Than from RLAI to Oral Antipsychotics 1. + Censored Injectable risperidone to injectable paliperidone Injectable risperidone to oral antipsychotic.8 Survival Probability.6.4 Cohort Number of Events Average Days under Hospitalization Average Days of Time at Risk Hazard Ratio 95% CI (P value).2 Injectable Risperidone to Injectable Paliperidone Injectable Risperidone to Oral Antipsychotic (.24) Time to Hospitalization (days) Propensity Score Matched Survival Analysis Voss EA, et al. Int Clin Psychopharmacol. 215;3(3): LAIs vs Oral Antipsychotics: Cohort Studies Hospitalization Risk (N = 29, n = 32,274) Statistics for Each Study Study Name Outcome Risk Ratio Lower Limit Upper Limit Z- Value P- Value Risk Ratio and 95% CI Chue 25 Hospitalization Risk Kim 28 Hospitalization Risk Conlon 22 Hospitalization Risk NCT Hospitalization Risk Pinto 2 Hospitalization Risk Bellido 28 Hospitalization Risk Barrio 213 Hospitalization Risk Baser 215 Hospitalization Risk Schreiner 214 Hospitalization Risk Tavcar 2 Hospitalization Risk Gutwinski 27 Hospitalization Risk Ju 214 Hospitalization Risk Hoiberg & Nielsen 26 Hospitalization Risk Calabresi & Marchetti 1983 Hospitalization Risk Varner 21 Hospitalization Risk Huang 213 Hospitalization Risk Chan 215 Hospitalization Risk Babiker 1987 Hospitalization Risk San 213 Hospitalization Risk Liu 215 Hospitalization Risk Cuidad 212 Hospitalization Risk Moore 1998 Hospitalization Risk Kelin 211 Hospitalization Risk Marchiaro 25 Hospitalization Risk Olivares 29 Hospitalization Risk Bitter 213 Hospitalization Risk Valevski 212 Hospitalization Risk Werneck 211 Hospitalization Risk Conley 23 Hospitalization Risk Overall Total N = 39, n = 59,796; follow-up = 18.9 ± 1.2 months. OAP = oral antipsychotic. Kishimoto T, et al. Under review Favors LAI Favors OAP LAIs vs Oral Antipsychotics: Cohort Studies All-Cause Discontinuation (N = 11, n = 22,715) Statistics for Each Study Study Name Outcome Risk Lower Upper Z- P- Ratio Limit Limit Value Value Risk Ratio and 95% CI Conlon et al. 22 All Cause Discontinuation Olivares et al. 29 All Cause Discontinuation Zhu et al. (SCAP) 28 All Cause Discontinuation Carpiniello et al. 211 All Cause Discontinuation Fe Bravo-Ortiz et al. 211 All Cause Discontinuation Kelin et al. 211 All Cause Discontinuation Bitter et al. 213 All Cause Discontinuation Chue et al. 25 All Cause Discontinuation Ibach & Schreiner 28 All Cause Discontinuation Haro et al. (SOHO) All Cause Discontinuation NCT All Cause Discontinuation Overall Total N = 39, n = 59,796; follow-up = 18.9 ± 1.2 months. Kishimoto T, et al. Under review. Favors LAI Favors OAP

11 LAI Antipsychotics vs LAI Antipsychotics Acute 13-Week Efficacy of Paliperidone Palmitate Comparable to Risperidone LAI PANSS Change from Baseline (LS Mean) Day Mean Doses: PP approx. 19 mg monthly RLAI approx. 31 mg q 2 weeks PP (n = 389) RLAI (n = 376) Endpoint Pandina G, et al. Prog Neuropsychopharmacol Biol Psychiatry. 211;35(1): Non-inferiority Trial vs Risperidone LAI Change in PANSS Total Scores (13 Weeks) Improvement Mean Change from Baseline (± SD) ± ± 15.4 PP (N = 25) RLAI (N = 28) In a Chinese schizophrenia patient population: Non-inferiority of PP to oral risperidone (RLAI arm) was observed as early as day 8 (the first assessment time point) Non-inferiority of PP to RLAI was demonstrated at every subsequent time point assessed Least-squares mean difference in PANSS total score: -2.3 points (95% CI: -5.3 to.63) between paliperidone palmitate and risperidone LAI Li H, et al. Prog Neuropsychopharmacol Biol Psychiatry. 211;35(4):12-18.

12 Paliperidone Palmitate vs Haloperidol LAI: Time to Efficacy Failure No. at Risk No. with Event Survival Probability Paliperidone Haloperidol Paliperidone Haloperidol Follow-up Time (months) Site-stratified log-rank P = Efficacy failure (independent committee): psychiatric hospitalization; need for crisis stabilization; meaningful increase in outpatient visits; inability to discontinue OAPs within 8 weeks due to insufficient benefit; discontinuation of LAI due to insufficient benefit; ongoing or repeated need for OAPs beyond 8 weeks. McEvoy JP, et al. JAMA Psychiatry. 214;311(19): HR =.98 (95% CI: ) Paliperidone Haloperidol Risperidone LAI vs FGA-LAIs (n = 4532, 27 patient years) Time to Hospitalization All Cause Discontinuation Survival (%) Survival (%) Years RIS-LAI FGA-LAI Years Zuclopenthixol decanoate = 52.2%, perphenazine decanoate = 37.2%, haloperidol decanoate = 5.%, flupenthixol decanoate = 4.4%, fluphenazine decanoate = 1.3%. FGA = first-generation antipsychotic. Nielsen J, et al. Schizophr Bull. 215;41(3): QUALIFY: Study Design Period A Period B Period C Safety Screening (<2 weeks) a Oral conversion IM treatment initiation IM treatment continuation, once-monthly follow-up (3 weeks) (5 weeks) (2 weeks) (4 weeks) Patients were randomized 1:1 R Oral Aripiprazole 5 3 mg/day (n = 143) Oral Paliperidone 3-12 mg/day (n = 143) Patients were converted from a previous antipsychotic Aripiprazole-OM 4 mg 1 week oral aripiprazole (1 3 mg/day) Injection 1: 4 mg aripiprazole-om 2 weeks oral aripiprazole (1 2 mg/day) Paliperidone IM injection Injection 1: 15 mg Xeplion or 234 mg Invega Sustenna Injection 2: 1 mg Xeplion or 156 mg Invega Sustenna in 1 week Aripiprazole-OM 4/3 mg 5 Injections Paliperidone IM injection (5 15 mg/month Xeplion or mg Invega Sustenna) Baseline Two visits (Weeks 2 & 3) Two visits (Weeks 4 & 8) Five Monthly Visits a Patients undergo screening for eligibility (7 14 days); patients stratified according to age > 35 or 35 years with expected ratio of 1:2. IM = intramuscular; R = randomization. Naber D, et al. Schizophr Res. 215;168(1-2):

13 QUALIFY: Patient Disposition Screening n = 381 Randomization n = 295 (77.4%) Screening failures n = 86 (22.6%) Patient met exclusion criteria: n = 55 Withdrawal of consent: n = 14 Did not meet inclusion criteria: n = 12 Lost to follow-up: n = 5 (3.6%) Non-compliance: n = 5 Other: n = 8 AOM 4 n = 148 PP n = 147 Not treated n = 4 (2.7%) Not treated n = 1 (6.8%) Adverse events: n = 16 (11.1%) Lack of efficacy: n = 8 (5.6%) Adverse events: n = 27 (19.7%) Lack of efficacy: n = 3 (2.2%) Completed Discontinued n = 1 (67.6%) n = 44 (29.7%) Withdrawal of consent: n = 7 (4.9%) Protocol violation: n = 6 (4.2%) Lost to follow-up: n = 2 (1.4%) Non-compliance: n = 1 (.7%) Completed n = 83 (56.5%) Discontinued n = 54 (36.7%) Withdrawal of consent: n = 12 (8.8%) Protocol violation: n = 4 (2.9%) Lost to follow-up: n = 5 (3.6%) Non-compliance: n = 1 (.7%) Other: n = 4 (2.8%) Other: n = 1 (.7%) AOM = aripiprazole once-monthly. Naber D, et al. Schizophr Res. 215;168(1-2): QUALIFY: Aripiprazole Once-Monthly vs Paliperidone Palmitate QLS Domains LSM Change from Baseline to Week 28 (SE) AOM 4 (n = 136) PP (n = 132) * Common Objects and Activities (2 items) Instrumental Role (4 items) Intrapsychic Foundations (7 items) Change in the Heinrich Carpenter Quality of Life Scale Domain Scores at 28 Weeks *P =.39. LSM = least squares means; QLS = quality of life scale. Naber D, et al. Schizophr Res. 215;168(1-2): Interpersonal Relations (8 items) QUALIFY: Aripiprazole Once-Monthly vs Paliperidone Palmitate QLS by Age Group LSM Change from Baseline to Week 28 (SE) Years AOM 4 (n = 41) 35 Years PP (n = 37) > 35 Years AOM 4 (n = 95) > 35 Years PP (n = 95) * * Treatment Week Change in the Heinrich Carpenter Quality of Life Scale Scores at 28 Weeks *P <.5. Naber D, et al. Schizophr Res. 215;168(1-2):

14 How to Choose an LAI 1. Is the patient demonstrating adequate efficacy and tolerability on oral fluphenazine, haloperidol, risperidone, paliperidone, olanzapine, or aripiprazole? Switch to the corresponding LAI formulation For patients receiving oral risperidone, can consider using paliperidone palmitate for convenience No requirement for oral supplementation upon initiation, less frequent injections, supplied in pre-filled syringes, smaller needle bore, lower injection volume, no refrigeration required, 3- month formulation now available for persons already receiving paliperidone palmitate For patients receiving oral fluphenazine or haloperidol, need to weigh the potential disadvantages of using concomitant oral anticholinergics for the management of motoric adverse effects These agents add complexity to the regimen (an oral tablet/capsule) Anticholinergic agents can interfere with memory and other cognitive functions 2. Is the patient being treated acutely and does not want oral medication? Consider LAI antipsychotics that do not require oral supplementation and where the clinical trials have demonstrated acute efficacy, either paliperidone palmitate or olanzapine pamoate Updated from Citrome L. Expert Rev Neurother. 213;13(7): How to Choose an LAI (cont d) 3. Are weight gain and metabolic adverse effects a concern for this individual patient? Consider aripiprazole monohydrate, paliperidone palmitate, or risperidone microspheres among the second-generation LAI antipsychotics, in that order Can consider the first-generation LAI antipsychotics as well 4. Is prolactin elevation a clinical concern for this individual patient? Consider aripiprazole monohydrate Avoid paliperidone palmitate, risperidone microspheres, or the first-generation LAI antipsychotics 5. Is cost the primary concern? The first-generation LAI antipsychotics may be the only option available 6. Are any of the following people or entities NOT enrolled in the Olanzapine Pamoate Patient Care Program: patient, prescriber, healthcare facility, pharmacy? Olanzapine pamoate cannot be used Updated from Citrome L. Expert Rev Neurother. 213;13(7): Patient Choice The need for patient involvement, empowerment, and choice is widely recognized Many clinicians may be unaware that their counseling style may stifle a patient s ability to ask questions Patients fear challenging the authority of their doctors or being labeled as difficult

15 Shared Decision Making Shared decision making means that you and your patients make medication choices within the evidence base Patients are supported to consider options. The goal is to achieve informed preferences The clinician and patient are equal partners. The decisions are made together Evidence-based medicine is used, but is tailored to the individual Elwyn G, et al. J Gen Intern Med. 212;27(1): Patients Do Choose LAI Antipsychotic Therapy When Properly Informed In a survey of psychiatrists: Patient refusal was cited as a primary reason for not prescribing LAI formulations In a survey of patients without experience with these agents: 79% cited having never been informed about the option by their psychiatrist 75% of psychiatrists felt that they informed the patient, but only 33% of patients felt informed Heres S, et al. J Clin Psychiatry. 26;67(12): Jaeger M, et al. Psychiatry Res. 21;175(1-2): Patients Do Choose LAI Antipsychotic Therapy When Properly Informed (cont d) In a survey of patients with > 3 months of experience with an LAI formulation: LAI antipsychotics were the preferred formulation 7% of patients felt better supported in their illness by virtue of regular contact with the doctor or nurse who administered their injection Caroli F, et al. Patient Prefer Adherence. 211;5:

16 Psychiatrists Cite Multiple Reasons for Not Prescribing LAI Formulations 1 Psychiatrists (%) % 8% 75% 71% 68% 58% 31% 1 Sufficient Adherence to Oral Patient Refusal Antipsychotic Not Available as LAI Costs of Drug EPS = extrapyramidal symptom. Heres S et al. J Clin Psychiatry. 26;67(12): Not Appropriate Option after Relapse Poorer Control of Effect Compared to Oral Drug High EPS Risk with LAI LAI Formulations: Balancing Pros and Cons for Patients Continuous antipsychotic coverage No need to remember Less conflict over suspected nonadherence Confidentiality Possibly decreased relapse & hospitalization rates More appointments with some agents Perceived stigma Conversion from oral to LAI Fear of pain Inflexible dosing / stopping Lack of experience Negative clinician appraisal Adapted from Correll CU. J Clin Psychiatry. 213;74(8):e16. Addressing Common Negative Perceptions Injections are a hassle à Depending on the medication you choose, it could be as infrequent as 4 a year. You won t have to remember to take meds every day Someone always nags me about taking my pills à Won t happen again Control over me à control over your illness

17 Addressing Common Negative Perceptions (cont d) What if I want to stop? à You can stop anytime, and if you do, there is less chance of a withdrawal reaction Means I m sicker à It actually means you are more likely to stay well Start with 1 injection and let s see how it goes Why not give it a try!? You might just like it! Summary LAI antipsychotics are superior to placebo in the acute and maintenance treatment of schizophrenia Superiority of LAI antipsychotics to oral antipsychotics depends on design and patient characteristics LAI antipsychotics do not seem to differ much regarding efficacy, but effectiveness and tolerability differences may be larger