Long-Acting Injectable Antipsychotics: Where Do They Fit in the - PowerPoint PPT Presentation

Long-Acting Injectable Antipsychotics: Where Do They Fit in the Treatment Plan? Christoph U. Correll, MD John Lauriello, MD

Objectives • Monitor adherence to antipsychotic treatment • Identify patients who may benefit from long-acting injectable, or LAI, antipsychotic treatment and present them with objective information on the risks and benefits • And, use LAI antipsychotics safely and effectively in patients with schizophrenia and related disorders

Felix • 33-year-old construction worker • Diagnosed with schizophrenia at age 30 • Treated with a second-generation antipsychotic (SGA), with good effect • “Was doing so well” he decided to stop the medication • Hospitalized for 2 weeks • Lost his job and had to move in with his parents

Importance of Relapse Prevention Multiple relapses and subsequent exacerbations can cause: • Increased burden on family and caregivers • Greater use of healthcare resources • Increased risk of suicide attempts • Long-term symptoms and disability • Decrease in treatment response • Progressive decline in brain function Higashi et al. Ther Adv Psychopharmacol. 2013;3(4):200–218. Emsley et al. BMC Psychiatry 2013;13:50.

Predictors of Relapse • Earlier onset of illness • Substance use disorder • Social functioning at baseline • More severe symptoms • Antipsychotic medication nonadherence (hazard ratio for an initial relapse, 4.89) Robinson et al. Arch Gen Psychiatry . 1999;56:241–247. Ascher-Svanum et al. BMC Psychiatry . 2010;10:2.

Link Between Adherence and Relapse Study population included patients with recent onset of schizophrenia, schizophreniform, or schizoaffective disorders 80 69% 70 Relapse Rate (%) 60 50 40 30 18% 20 10 0 Poor Good Adherence With Oral or Depot Antipsychotics (N=50) Morken et al. BMC Psychiatry. 2008;8:32.

Factors Influencing Treatment Adherence Illness severity Frequency of treatment (how often is medication taken) Relationship with family Side effects Relationship with physician Cost of treatment Treatment setting Attitudes toward treatment (inpatient/outpatient) (physician/patient) Kane et al. World Psychiatry . 2013;12(3):216–226.

Methods for Monitoring Medication Adherence • Patient/family report Patient-Related • Self-assessment questionnaires • Diaries Pill count Clinical response • • Physician-Observed Prescription refills If injectable agent, • • missed shot • Serum drug levels (blood draws/hair analysis) Physiologic • Adverse events • Biomarkers • Electronic pill trays Electronic • Medication event monitoring system cap • Medication event marker Kane et al. World Psychiatry . 2013;12(3):216–226.

First-Year Outcomes After Discharge N=56 70% of patients who discontinued 26 patients 30 patients antipsychotics continued discontinued relapsed within the treatment (46%) treatment (54%) first year 9 patients who 21 patients who discontinued discontinued treatment did not treatment relapsed relapse (30%) (70%) Novak-Grubic & Tavcar. Eur Psychiatry. 2002;17(3):148–154.

Rachel • 55-year-old woman with schizophrenia (since age 25) • Tried multiple first-generation antipsychotics (FGAs) when first diagnosed • Always stopped them secondary to EPS • Finally, she was convinced to try an SGA, with no EPS noted • But, at her 3-month follow-up, she had stopped the SGA

Oral Atypical Medications Have Not Solved the Issue of Nonadherence Typical Antipsychotics 12-Month Adherent Fill Rate (%) Perphenazine Haloperidol 0 20 40 60 80 100 Atypical Antipsychotics Quetiapine Olanzapine Risperidone 0 20 40 60 80 100 Dolder et al. Am J Psychiatry . 2002;159(1):103–108.

Antipsychotic Drugs Versus Placebo Relapse • Number needed to treat (NNT) for relapse prevention= 3 • 27% relapse with antipsychotic drugs vs 64% with placebo Readmission • NNT= 5 • 10% readmission with antipsychotics vs 26% with placebo Employment rate did not differ between antipsychotic and placebo groups Leucht et al. Lancet . 2012;379(9831):2063–2071.

Continuous Versus Intermittent Antipsychotic Treatment Meta-analysis of randomized controlled trials (RCTs) with FGAs and SGAs in stabilized patients with schizophrenia, 1950–2014 Risk of relapse: Compared with continuous treatment, 3 times greater with intermittent treatment and 6 times greater with placebo De Hert et al. CNS Drugs . 2015;29(8):637–658.

Pros and Cons of LAIs Perceived Advantages Perceived Disadvantages No need for daily medication Reluctance to get shots Ease of compliance monitoring Potential for injection-site complications Stable plasma levels No rapid dose adjustments Reduced risk for Different side effects (eg, relapse/rehospitalization anxiety, akinesia, cholesterol) Fewer dose-related side effects (eg, extrapyramidal) Fleischhacker et al. Managing Schizophrenia: The Compliance Challenge . 2nd ed.; 2007. Misawa et al. Schizophr Res . 2016 Oct;176(2–3):220–30.

Characteristics of FGA and SGA LAIs Oral Dose Postinjection Antipsychotic Base Supplementation Time to Peak Interval Observation Needed Fluphenazine Oil Varies No 2–4 days No decanoate FGAs Haloperidol Oil 4 weeks No 6–7 days No decanoate Risperidone Water 2 weeks 3 weeks 4–6 weeks No microspheres Olanzapine pamoate Water 2 or 4 weeks No 4 days At least 3 hours Paliperidone Water Monthly No 13 days No SGAs palmitate Paliperidone Water Every 3 months No 30–33 days No palmitate (ER) Aripiprazole Water Monthly 2 weeks 5–7 days No monohydrate Aripiprazole lauroxil Water Monthly or 3 weeks 4 days No (ER) every 6 or 8 weeks Correll et al. J Clin Psychiatry. 2016;77(suppl 3):1–24.

Efficacy of LAIs Response: • NNT=4 for SGA LAIs vs placebo • No difference for SGA LAIs vs oral antipsychotics Fusar-Poli et al. Int Clin Psychopharmacol . 2013;28(2):57–66

Adverse Effect Differential Antipsychotic EPS Weight QTc Sedation Prolactin Gain Prolongation Elevation Haloperidol Marked Mild Mild Moderate Moderate Risperidone Moderate Moderate Moderate Moderate Marked Moderate Moderate Mild Mild Marked Paliperidone No effect Marked Mild/Moderate Moderate/ Mild Olanzapine Marked Mild Mild No effect/Mild Mild No effect Aripiprazole Leucht et al. Lancet . 2013;382(9896):951–962.

Adverse Effects With LAI vs Same Oral Antipsychotics • Study included 16 RCTs • 119 adverse effects were studied • 115 adverse effects did not differ significantly between LAIs and oral antipsychotics • LAIs were associated with significantly more anxiety, akinesia, and low-density lipoprotein cholesterol change, but also with significantly lower prolactin change Misawa et al. Schizophr Res. 2016 Oct;176(2-3):220 –2 30.

PROACTIVE Study • N=305; schizophrenia or schizoaffective disorder • LAI risperidone vs oral SGA of clinician’s choice • 30 months • No significant treatment difference in time to relapse or hospitalization • Limitations: no focus on previously nonadherent patients, biweekly monitoring, greater flexibility in oral treatment Buckley et al. Schizophr Bull. 2015;41(2):449–459.

LAI vs Oral Antipsychotics Meta-analysis of 25 mirror-image studies showed that LAIs were associated with less hospitalization than oral agents Hospitalization Risk Number of Hospitalizations Risk 0.430 Rate 0.381 Ratio Ratio Lower 0.350 Lower 0.283 Limit Limit Upper 0.527 Upper 0.512 Limit Limit Z Value -8.074 Z value -6.397 P Value .0000 P Value .0000 Kishimoto et al. J Clin Psychiatry . 2013;74(10):957-965.

CUtLASS Study • Patients with schizophrenia who had poor antipsychotic response were randomly assigned to treatment switches and followed for 1 year • 43% of patients were taking LAIs before randomization (n=155) • For patients with inconsistent adherence, switching from LAI to oral antipsychotic was associated with poorer outcomes (symptoms, functioning, quality of life) than switching from one oral agent to another • For patients who were consistently adherent, no significant change was noted between LAI-to-oral and oral-to-oral switches Barnes et al. Br J Psychiatry. 2013;203(3):215–220.

Switching from LAI to LAI or Oral Antipsychotic • Patients who switched from risperidone LAI to paliperidone LAI had fewer relapse-related events (eg, hospital visits) than patients who switched to an oral antipsychotic (26 vs 32) • Patients also had a longer time to an event when switched to the paliperidone LAI (70 vs 47 days) Voss et al. Int Clin Psychopharmacol . 2015; 30(3): 151–157.

Josh • 21-year-old college student • Joined a fraternity, began smoking marijuana • Brought to emergency department by campus police for behaving strangely (second time this semester) • Had been prescribed an antipsychotic the first time, but did not take it once released from the hospital

Clinical Predictors of Poor Outcomes Fixed Risk Factors Modifiable/Preventable Risk Factors Male sex Longer duration of untreated psychosis Earlier illness onset Greater number of relapses Premorbid developmental delay Comorbidities (eg, substance use) Longer illness duration Early nonresponse to antipsychotic medication Greater severity of illness Nonadherence Carbon & Correll. Dialogues Clin Neurosci . 2014;16(4):505–524.