Srivastava, Amresh

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Switching and Selecting Atypical Antipsychotic Drugs: Paliperidone

Western UniversityScholarship@WesternPsychiatry Presentations Psychiatry Department6-5-2009Switching and Selecting Atypical AntipsychoticDrugs: PaliperidoneAmresh SrivastavaUniversity of Western Ontario, amresh.srivastava@sjhc.london.on.caFollow this and additional works at: https://ir.lib.uwo.ca/psychiatrypresPart of the Psychiatry and Psychology CommonsCitation of this paper:Srivastava, Amresh, "Switching and Selecting Atypical Antipsychotic Drugs: Paliperidone" (2009). Psychiatry Presentations. 23.https://ir.lib.uwo.ca/psychiatrypres/23Switching and selecting atypical antipsychotic  drugs:PaliperidoneAmresh SrivastavaAssistant Professor of PsychiatryThe University of Western Ontario, LondonAssociate Scientist, Lawson health research InstitutePhysician Assessment Program, Regional Mental health care, St.ThomasPhysician Team Leader, Early Psychosis Program, Elgin ( E-PEPP)Disclosure • Research, education & travel grant. Speakers group & advisory panels:• Janssen Cilag• Janssen Ortho• Astra zeneca.Canada & UK• Pfizer• Roche pharmaceuticals• Nicolus Pharmaceuticals• SUN Pharma• Prempharma• Elli LilyLearning objectives• Needs and problems of switch• Evidence about efficacy of switch• Paliperidone • Clinical practice of switching antipsychoticsPharmacokinetics vs. PharmacodynamicsDrugdosePlasmaconcentrationTissueconcentrationPharmacologicaleffectsMetabolitesExcretion of drugs andmetabolitesBehavioral effectsVariability is the major determinant of the dose-effect relationship in patientsD2-Receptor Occupancy Fluctuation with Simulated Repeated DosingKarlsson P et al., PosterIR 3 mg/d: Fluctuation = 64 – 83%ER 6 mg/d: Fluctuation = 75 – 78%What is the prescribing patternBret P, Bret MC, Queuille E.  Prescribing patterns of antipsychotics in 13 French psychiatric hospitals.Encephale. 2009 Apr;35(2):129-38.SGAs have become the first-line treatment for psychiatric disorders.CaseQ2 To which APD Switch to PaliperidoneSwitch to PaliperidoneCOMBINATION ATYPICALS: 1.Suzuki.T, Human psychopharmacology 2008; 23:455-4632.Chan J, Journal of Psychopharmacology21(6) (2007) 657-664• Side effect   • Lack of efficacy• Appropriate setting• Social support• Risk factors • Inpatient set up• Outpatients    Switch:when do we change APD?How to select new APDAcute EpisodeRelapseSelecting Antipsychotics Why do patients discontinue medication? CATIE 1Weiden PJ.J.Clin Psychiatry 2007;68 [suppl 1]:12-19CATIE – Phase 3, Symptom responseDrugs ARIP CLOZ COMB FLU-D OLAN PERP QUET RISP ZIPR P-valuePANSS –3 months0.506 0.002✓0.002 0.005✓0.002✓0.084 0.013 0.044 0.045 0.832✖PANSS-6✔✔0.006 <0.001✔0.43 0.003✔0.018 0.100 0.009 0.371 0.515✖• Outcome of switch is  dependent upon– Medication switched to– Medication switched from.•Model of factors that influence decisionWeiden PJ, J.Clin.Psychiatry, 2007;68(suppl 1)Criteria's for Response • Considerable divergence of expert opinion• One survey of experts indicated that a period of 2.6 to 5.5 weeks was required.• Lack of minimal response after 1 or 2 weeks is a powerful Predictor of subsequent poor response   6 weeks         12 weeks                  ???APA Working group 2005Symptom, Severity & Duration: A dimensional approach Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies.Emsley R, Berwaerts J, Eerdekens M, Kramer M, Lane R, Lim P, Hough D, Palumbo J.Int Clin Psychopharmacol. 2008• This analysis shows that paliperidone extended-release can maintain improvements in symptoms and functioning and is generally well tolerated for up to 52 weeks in schizophrenia patients.Kramer et al. J Clin Psychopharmacol, 2007p<0.001 paliperidone vs. placeboPaliperidone: Delayed Symptom RecurrenceDoes the remission sustain??Randomized, Double-Blind, Placebo-Controlled Study of Paliperidone Extended-Release and Quetiapine in Inpatients With Recently Exacerbated SchizophreniaCanuso CM, Dirks B,  Randomized, Double-Blind, Placebo-Controlled Study of Paliperidone Extended-Release and Quetiapine in Inpatients With Recently Exacerbated Schizophrenia. Am J Psychiatry. 2009 May 1 Is paliperidone better than other AAPD?For which symptom domain it works best?Direct and indirect effects of paliperidone extended-release tablets on negative symptoms of schizophrenia.Turkoz I, Bossie CA, Dirks B, Canuso CM.Ortho-McNeil Janssen Scientific,: Neuropsychiatr Dis Treat. 2008 Oct;4(5):949-58• Path analysis indicated that up to 33% of negative symptom improvement was a direct treatment effect.• Negative symptom improvement also was indirectly mediated via changes in positive and depressive symptoms.Expected clinical benefits of paliperidone extended-release formulationwhen compared with risperidone immediate-release.Pani L, Marchese G.Expert Opin Drug Deliv. 2009Is it same or better than RisperidoneKW, 20 years, FES admitted 3 weeks, discharged in ‘good remission’ Olan 10 mg BID, April 2008Partial or No ResponseTexas Algorithm, 2006 What are evidence-based recommendations for selecting Antipsychotic medication?Consider earlier trail of clozapine in atients with a H/O recurrent suicidality, violence, or comorbid substance abuse. Persistence of positive symptoms > 2years warrants & >5 years requires a clozapine trial, independent of number of  antipsychotic trials.Benefits of switching Antihistaminic Effects of AntipsychoticsAdapted from Weiden, P. J., 2007* Sedation is dose-related and usually abates after several weeks.†Sedation also possible; insomnia usually abates after several weeks.ClozapineQuetiapine*Olanzapine*RisperidoneHaloperidolZiprasidone †Aripiprazole †InsomniaSedation}}Incidence of Cardiac Adverse Events Occurring in ≥ 5% of Patients, n (%)AE PlaceboN=3553 mgN=1276mgN=2359mgN=24612mgN=24215mgN=113Tachycardia 10 (3) 3 (2) 17 (7) 18 (7) 18 (7) 2 (2)Sinus Tachycardia15 (4) 11 (9) 9 (4) 10 (4) 17 (7) 8 (7)QTc Prolongation9 (3) 4 (3) 9 (4) 7 (3) 12 (5) 4 (4)Paliperidone ER GroupsMeltzer et al. ICOSR 2007No clinically relevant difference between proportions of QTc in pali vs. placebo groups (1.6% vs. 1.4%)EPS-Related Adverse EventsPlacebo 3mg 6mg 9mg 12mg 15mgPercent 11 13 10 25 26 24Paliperidone ER GroupsDepot Injections• Paliperidone ER 12 mg/day was superior to placebo from baseline in YMRS score , from day 2 to endpoint. • Paliperidone 3,6 & 12 mg were safe well tolerated in patients with bipolar I disorder experiencing acute  manic or mixed episode.• Initiated as 150 mg eq. IM deltoid injection, • Achieved plasma concentration associated with effective symptom control.• Subsequent monthly dosing maintained clinically and statistically effective response across 25-150 mg.eqBipolar Disorder Switching to a new medication yielded no advantage over staying on the previous medication. Staying on olanzapine was associated with greater weight gain. Outcome switching: CATIE, 2009 Clinical benefit in switching antipsychotics• Previous CATIE demonstrated equal efficacy in Head-head trial• This study reiterates equal benefit in switching• Limitations• Subjects were not ‘unresponsive' dose, duration of previous APD was not known, so ‘mirror-image’ comparison was not possibleWeight Gain Comparisionof Atypical AntipsychoticsIncidence of ≥7% Increase in Body Weight in Short-Term Trials*5.17.99.818.023.029.03.75.04.09.06.03.0051015202530Aripiprazole** PaliperidoneER***Ziprasidone Risperidone Quetiapine OlanzapinePercent of Patients (%)Placebo*Based on United States Product Inserts**Error bars reflect reporting of weight gain in PI by baseline BMI***confirmation of US PI1 in 31 in 41 in 51 in 101 in 121 in 19Metabolic profiles of second-generation antipsychotics in early psychosis: Findings from the CATIE study.2009Patel JK, Buckley PF  Metabolic profiles of second-generation antipsychotics in early psychosis: Findings from the CAFE study.Schizophr Res. 2009 Jun;111(1-3):9-16. Epub 2009  (J Clin Psychiatry 2007;68[suppl 4]:34–39) WHO IS A CANDIDATE FOR SWITCHING?Expert Consensus Guidelines recommend the combination of psychosocial interventions plus a trial switch to an antipsychotic with less weight gain liability. Monitoring GuidelinesSide effects of AntipsychoticsSeizure, Arrhythmias, Blood count, Prolactin, Weight , & Metabolic• Atypical antipsychotic drugs and the risk of sudden cardiac Death ,– LH . N Engl J Med. 2009 May 14;360(20):2137;[Potentially lethal cardiac side effects caused by psychiatric drugs] Sawicke L, Sturla S.Vertex. 2008 Nov-Dec;19(82):387-93• [Hematological adverse effects caused by psychiatric drugs  – Mazaira S.Vertex. 2008 Nov-Dec;19(82):378-86• Akathisia and second-generation antipsychotic drugs– Kumar R, Sachdev PS. Curr Opin Psychiatry. 2009 May;22(3):293-99.• Antipsychotic agents and cardiometabolic morbidity in youth. – Kruszewski SP, Paczynski RP.Arch Pediatr Adolesc Med. 2009 Apr;163(4):394-5; author reply 395• Weight gain, metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol.– Krakowski M, Czobor P, Citrome L.Schizophr Res. 2009 May;110(1-3):95-102• Association between antipsychotic drugs, antidepressant drugs, and venous thromboembolism.– Lacut K.Clin Adv Hematol Oncol. 2008 Dec;6(12):887-90.• Antipsychotic-induced hyperprolactinemia.– Bostwick JR, Guthrie SK, Ellingrod VL.Pharmacotherapy. 2009 Jan;29(1):64-73.SWITCHING STRATEGIES FOR ANTIPSYCHOTIC MEDICATION Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes. J Clin Psychiatry 2007;68(suppl 6):10–13  Switching only changes nature of Problem• Do’s ( check list ) – Measuring clinical condition– Physical health– Base line investigation ( EKG, Blood work )– Explain – Review all medications – Attention to D-D-I ( take help from Pharmacist)– Read new information – Monitor – Frequent appointment• Quantification and measurement in psychosis– SAPS-SANS– PANSS– BPRS– HDRS– ADL– GAF– QOLClinical Consequences of switching• Good experience for every one– Do not reduce the level of monitoring– Late consequences and     Risk of non-compliance.• Into bigger problem– Withdrawal symptoms of antipsychotic– Increase in secondary symptoms ( anxiety-insomnia)– Persisting side effects of prior APD– Emergence of new psychiatric symptoms– Side effects of newer APD– Break-through Psychosis– Fall, giddiness, fainting, – Emergency situation ( Seizure, low blood count, Cardiac event, Steven-Johnston)Differences in effects on fasting triglyceride levels were also found between agents in a short, open-label, parallel- group   SWITCHING STRATEGIES Pfizer Inc. Briefing Document for Zeldox Capsules (zipra- sidone HCl). Submitted to FDA Psychopharmacological Drugs Advisory Committee; July 19, 2000. Available at: http://www.fda.gov/ohrms/dockets/ac/00/backgrd/ 3619b1a.pdf. Accessed Dec 15, 2006 Determinants of outcome in schizophreniaRelapseDrug DiscontinuationNon-adherence is a sign of Partial or Complete Non-responseNon-adherence or discontinuation is associated (marker) of poor efficacyFinal message • Switching should be NOT be a priority situation.• It does not give any superiority in terms of efficacy amongst SGA except clozapine• Outcome of switch depends upon both the previous and the new molecule• The first clinical option should be optimization of dose, schedule, education & non-drug therapies.• It should be opted only if clinical conditions are compelling• Whenever switch, due consideration should be given to all denominators of its outcome.• Not to compromise efficacy • Not to continue with side effects

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Switching and Selecting Atypical Antipsychotic Drugs: Paliperidone

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