Handout for the Neuroscience Education Institute (NEI) online activity: Clinician's Guide to Prescribing Depot Antipsychotics Copyright © 2012 Neuroscience Education Institute. All rights reserved. Learning Objectives • Explain the benefits and risks of depot antipsychotics • Optimize the utilization of individual depot antipsychotics Copyright © 2012 Neuroscience Education Institute. All rights reserved. Pretest Question 1 Sarah is a 24-year-old patient with schizophrenia. She has a history of treatment non-adherence due to an aversion to swallowing pills. Which of the following antipsychotics is currently available in a long-acting injectable formulation? 1. Asenapine 2. Olanzapine 3. Iloperidone 4. 1 and 2 only 5. 2 and 3 only Copyright © 2012 Neuroscience Education Institute. All rights reserved. Pretest Question 2 Mark is a 41-year-old patient with schizoaffective disorder. He has been taking the depot formulation of paliperidone (Invega Sustenna, 234 mg) for the past 2 years. Unfortunately, Mark has missed his last 2 appointments and consequently has not been administered antipsychotic treatment for approximately 8 weeks. How should paliperidone palmitate be reinitiated in this patient? 1. Initiate daily oral paliperidone followed by a 234-mg paliperidone injection 1 week later 2. Initiate patient with a 156-mg paliperidone palmitate injection followed by another 156-mg injection 1 week later 3. Immediately resume the previously established 234-mg paliperidone palmitate injection Copyright © 2012 Neuroscience Education Institute. All rights reserved. Pretest Question 3 Ike is a 61-year-old patient with schizophrenia who is currently only partially adherent to his daily oral haloperidol treatment (5 mg/day). He has agreed to try the depot formulation of haloperidol (haloperidol decanoate). In order to achieve optimal plasma levels of haloperidol, the monthly injected dose of haloperidol decanoate should be: 1. 50 mg/month 2. 100 mg/month 3. 200 mg/month Copyright © 2012 Neuroscience Education Institute. All rights reserved. Why Use Long-Acting Injectable Antipsychotics? Advantages Disadvantages • Assured medication delivery and continuous antipsychotic coverage • No need to remember to take medication every day • Clinician can be immediately notified of non- adherence • Drug remains in system for weeks after a missed dose • Reduce relapse frequency and rehospitalization rates • Avoidance of first-pass metabolism, so there is a better relationship between dose and blood level of drug • Cost/insurance coverage • Lower peak plasma level may be associated with • Oral to LAI conversion reduced side effects • Perceived stigma • Peak plasma level occurs less often, so may lead • Negative perception/stigma to reduced side effects • Lack of personnel to administer depot Gerlach. Int Clin Psychopharmacol 1995;9(5):17-20. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Impact on Clinical Decisions • Oral antipsychotics – Unknown compliance may prevent evaluation of medication effectiveness • Change medication? • Increase dose? • Augment? • Long-acting injectables – Known adherence allows for evaluation of medication effectiveness – Missed dose can trigger intervention – Patient–clinician interaction Barnes TRE, Curson D. Drug Safety 1994;10:464-79; Urquhart J. Clin Pharmacokinet 1994;27:202- 15; National Association of State Mental Health Program Directors. Technical Report on Psychiatric Polypharmacy; 2001. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Depot Injections Are Associated With a 50-65% Lower Risk of Rehospitalization Than Their Oral Counterparts Tiihonen J et al. Am J Psychiatry 2011;168:603-9. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Do Depot Antipsychotics Reduce Relapse Risk? Meta-analysis Conclusions: relative and absolute relapse risk reductions of 30% and 10%, respectively (RR 0.70, CI 0.57-0.87, NNT 10, CI 6-25, P=0.0009) Leucht C et al. Schizophr Res 2011;in press. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Not All Studies Show Superiority of Depot Antipsychotics Rosenheck RA et al. N Engl J Med 2011;364:842-51. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Relapse Risk: Oral vs. Depot Antipsychotics in Mirror Image Studies # of Hosp Days: # of Hosp Days: Study N Tx Duration p Oral Depot Denham & Anderson 103 12-40 mos 8,719 1,335 10-15 (1973) Devito et al. (1978) 122 1 yr 3,329 314 10-2 Freeman (1980) 143 12 yrs 19,510 4,376 10-25 Gottfries & Green 36 2-6 yrs 12,390 2,940 10-4 (1974) Marriott & Hiep 131 1 yr 12,434 5,619 10-5 (1976) Tegler & Lehmann 78 5 yrs 19,110 3,276 10-5 (1981) Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Pipothiazine Zuclopenthixol* 2-3 wks 4 wks 2-4 wks Haloperidol Flupenthixol* 4 wks 1-4 wks * Not available in the United States CONVENTIONAL DEPOTS Fluphenazine decanoate Haloperidol decanoate Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate Copyright © 2012 Neuroscience Education Institute. All rights reserved. Haloperidol Decanoate Copyright © 2012 Neuroscience Education Institute. All rights reserved. Ester Depot Disposition Esterified drug Injection in oil Metabolism to active Esterified drug Active drug & inactive metabolites in plasma Multicompartment CSF Renal & tissue binding biliary excretion Receptor binding Copyright © 2012 Neuroscience Education Institute. All rights reserved. Preparations and Basic Kinetics T T T 1/2 1/2 max (days) Drug Vehicle Dosage (days) (days) Multiple Single Dose Dose Fluphenazine Sesame 12.5-100 mg/ 0.3-1.5 6-9 14 decanoate oil 2-6 weeks Haloperidol Sesame 25-400 mg/ 3-9 ? 21 decanoate oil 4 weeks Davis JM et al. Drugs 1994;47(5):741-73. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Understanding Depot Kinetics • Rate-limiting step for drugs is slow absorption from the injection site • The observed terminal phase decline in plasma levels of fluphenazine decanoate corresponds to a half-life of 8-14 days rather than the elimination half-life of 15-24 hours • For haloperidol decanoate, the observed terminal half- life is 19-21 days rather than 15-24 hours • This pharmacokinetic action is called flip-flop kinetics and is the basis for understanding appropriate dosing with the older depot medications Ereshefsky L, Mascarenas CA. J Clin Psychiatry 2003;64(suppl 16):18-23. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate: Single-Dose Pharmacokinetics Paliperidone palmitate1 Risperidone long-acting injection25-mg dose2 Haloperidol decanoate3 Fluphenazine decanoate4 normalized to a 2.5-micromol/kg dose 25-mg dose Ereshefsky L, Saklad SR, Jann MW. J Clin Psychiatry 1984;45(suppl):50-8. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate: Chronic Dosing (25 mg/2 wks) Glazer WM. Schizophr Res 1988;1:425-99. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate: Chronic Dosing (25 mg/2 wks) 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 Flu (ng/mL)Level 0.2 0 2 4 8 12 26 38 52 64 78 90 104 Week Baseline Marder SR. Br J Psychiatry 1991;158:658-65. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate: Conversion From Oral • Formulas are less reliable than haloperidol oral depot • Schooler (1976): 10 mg/day oral = 12.5 mg IM q 3 wks • Ereshefsky (1985): 1.6 times the oral daily dose in mg/day as a WEEKLY injection for the first 4-6 weeks, then conversion to less frequent intervals Schooler N. Pharmacopsychiatry 1976;9:159-69; Jann et al. Clin Pharmacokinet 1985;10:315-33. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate: Chronic Dosing (50 mg/week) Jann et al. Clin Pharmacokinet 1985;10:315-33. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Probability Curves of Response and Disabling Side Effects by Plasma Fluphenazine Level Improvement Disabling side effects Adverse effects Response Van Putten T. J Psychiatr Neurosci 1994;19(4):254-64. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Fluphenazine Decanoate: Extended Interval Dosing Percentage of Schizophrenia Outpatients Who Remained Clinically Stable While Receiving 25 mg Every 2 Weeks (N=25) or Every 6 Weeks (N=25) Carpenter WT et al. Am J Psychiatry 1999;156(3):412-8. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Preparations and Basic Kinetics T T T 1/2 1/2 max (days) Drug Vehicle Dosage (days) (days) Multiple Single Dose Dose Fluphenazine Sesame 12.5-100 mg/ 0.3-1.5 6-9 14 decanoate oil 2-6 weeks Haloperidol Sesame 25-400 mg/ 3-9 ? 21 decanoate oil 4 weeks Davis JM et al. Drugs 1994;47(5):741-73. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Haloperidol Decanoate: Concentration vs. Time Mean monthly dose = 243 mg Ereshefsky L. Haldol decanoate [promotional materials]. McNeil Pharmaceuticals; 1988. Copyright © 2012 Neuroscience Education Institute. All rights reserved. Haloperidol Decanoate: Conversion From Oral • Studies using 10, 20, and 30 times the oral daily dose have been performed • 20 times the oral daily dose provided optimum plasma concentrations DURING THE EARLY PHASE OF TREATMENT – Oral haloperidol bioavailability is 65% (range 60-70%) – Example: patient on 10 mg/day x 30 days x 65% = 195 mg/month ~ 20 times oral daily dose • Over time, may be able