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  • Drug Response Dependent on 3 Variables As noted above. Reference Preskorn S. The slippery slide. J Pract Psychiatry Behav Health . 1999;5:50-55.
  • The fact that younger age predicted polypharmacy is difficult to explain given treatment recommendation of lower doses for first-episode patients. One possible explanation may be that schizophrenia can be associated with more florid symptoms in younger patients
  • Polypharmacy+in+Schizophrenia

    1. 1. Antipsychotic Combinations or ‘Polypharmacy’ Rationale Combination Antipsychotic Medication Usage
    2. 3. “ These Are but Shadows of the Things That Have Been,'' Said the Ghost. A Christmas Carol Charles Dickens
    3. 5. Polypharmacy <ul><li>The use of two or more medications to treat the same condition, the use of two or more drugs of the same chemical class, or the use of two or more drugs with the same or similar pharmacological actions to treat different conditions. </li></ul>
    4. 6. <ul><li>“ Trifluoperazine has been prescribed </li></ul><ul><li>with chlorpromazine in the treatment of </li></ul><ul><li>patients who fail to respond to one or </li></ul><ul><li>the other drug alone, where motor </li></ul><ul><li>activity is desirable, or as a means of </li></ul><ul><li>avoiding the toxic effects of high dosages </li></ul><ul><li>of either drug when given alone” </li></ul><ul><li>Kolb </li></ul><ul><li>Modern Clinical Psychiatry (1973) </li></ul>
    5. 7. <ul><li>“ No combination of phenothiazines is more effective than Thorazine alone. Polypharmacy, with the possible exception of perphenazine-amitriptyline, is no more effective than a single drug, but can lead to more side effects, errors in taking medication, and problems in dose adjustment in case of toxicity or change in clinical state.” </li></ul><ul><li>“ The Fourth Psychoactive Usage Guide” Appleton </li></ul><ul><li>Journal of Clinical Psychiatry </li></ul>
    6. 8. <ul><li>Less than half of the patients </li></ul><ul><li>under </li></ul><ul><li>Treatment for schizophrenia… </li></ul><ul><li>are </li></ul><ul><li>receiving proper doses of </li></ul><ul><li>antipsychotic medications or </li></ul><ul><li>appropriate psychosocial </li></ul><ul><li>interventions. </li></ul><ul><li>NIMH Schizophrenia Bulletin 1998***** </li></ul>
    7. 9. Antipsychotic Combinations vs. Monotherapy in Schizophrenia
    8. 10. Increasing use of Polypharmacy <ul><li>Reports of the prevalence of antipsychotic polypharmacy in the U.S. vary from 7% to 50% (prevalence rates of 20%) </li></ul><ul><li>Studies have shown a trend toward the increasing use of polypharmacy in the same treatment settings over time, despite the fact that evidence-based treatment guidelines recommend antipsychotic co-treatment only after unsuccessful attempts of multiple monotherapies, including clozapine. </li></ul>Miller AL et al. Clin Psychiatry (2004) 65:(4):500–508
    9. 11. Drug Response Dependent on 3 Variables: 2. Drug Concentration Absorption Distribution Metabolism Elimination 1. Affinity Receptors Enzymes Uptake Pumps 3. Patient Genetics Age Disease Environment Clinical Response Adapted from Preskorn S. J Pract Psychiatry Behav Health . 1999;5:50-55.
    10. 12. Antipsychotic polytherapy - Relevance <ul><li>Antipsychotic polytherapy was present in 20% and was significantly more likely in patients with schizophrenia and those treated with clozapine, quetiapine or ziprasidone. </li></ul><ul><li>Compared with antipsychotic monotherapy, polytherapy was associated with elevated rates of metabolic syndrome (50.0% vs. 34.3%) & TG/HDL (50.7% vs. 35.0%,). </li></ul>Correll et al. Schizophr Res. 2007;89(1-3):91-100.
    11. 13. Antipsychotic polytherapy - Relevance <ul><li>Compared with patients receiving antipsychotic monotherapy, patients on antipsychotic polytherapy have higher rates of metabolic syndrome and lipid markers of insulin resistance. </li></ul><ul><li>However, antipsychotic polytherapy is not independently associated with the prevalence of these abnormalities, which are related to known demographic, clinical and anthropometric risk factors. </li></ul>Correll et al. Schizophr Res. 2007;89(1-3):91-100.
    12. 15. Antipsychotic Combinations vs Monotherapy Christoph Et al. Schizophrenia Bulletin. 2008
    13. 16. Finding of superior efficacy of antipsychotic co-treatment <ul><li>antipsychotic combinations were superior to monotherapy even when using a cutoff score of &quot;much improved&quot; on the CGI and by the relatively low NNT in the efficacy analyses that ranged mostly between 5 and 7 </li></ul><ul><li>In 12 of 18 subgroup analyses, antipsychotic combinations were associated with significantly greater efficacy compared with monotherapy. </li></ul><ul><li>Exceptions were studies with trial durations of <10 weeks and conducted outside of China, as well as those that used combinations after non-response to monotherapy rather than right from the start </li></ul>Christoph Et al. Schizophrenia Bulletin. 2008
    14. 17. Antipsychotic augmentation strategies <ul><li>Positive effects for the antipsychotic polypharmacy were apparent the most in patients with acutely exacerbated schizophrenia and those who had 2 antipsychotic s started at the same time. (scenarios that have not been investigated except in studies conducted in China.) </li></ul><ul><li>Meta-analysis also found that antipsychotic co-treatments are superior in the 6 studies ( n = 394) lasting > 10 weeks (NNT = 5) but not in the studies lasting <10 weeks </li></ul><ul><li>4 of 6 studies lasting 10 weeks included a combination of clozapine plus either sulpiride ( N = 3) or risperidone ( N = 1). Therefore, it remains to be tested whether combinations that involve antipsychotic s other than clozapine are significantly more effective than monotherapy </li></ul>Christoph Et al. Schizophrenia Bulletin. 2008
    15. 18. Clozapine co-initiated <ul><li>In acutely exacerbated patients with confirmed refractory schizophrenia, clozapine could be co-initiated with a second antipsychotic in patients who stopped their prior antipsychotic due to nonadherence or experienced a significant exacerbation despite treatment with a non-clozapine antipsychotic </li></ul>Christoph Et al. Schizophrenia Bulletin. 2008
    16. 19. Algorithm Philosophy <ul><li>Goal of treatment should be remission </li></ul><ul><li>Most efficacious/safest treatments first-(i.e., evidence based) </li></ul><ul><li>Simplest interventions first </li></ul><ul><li>Subsequent interventions tend toward increased complexity & increased risk </li></ul><ul><li>Multiple options when appropriate </li></ul><ul><li>Patient preference </li></ul>
    17. 20. Some Causes of Polypharmacy: <ul><li>Irrational and Unjustifiable </li></ul><ul><li>Fear & Laziness </li></ul><ul><li>Sloppy Diagnosis </li></ul>
    18. 24. ALGORITHM - Aligning the Arrows <ul><li>A step-by-step procedure for solving a problem or accomplishing some end </li></ul>
    19. 25. PennMAPS Antipsychotic Algorithm
    20. 26. PennMAPS Antipsychotic Algorithm (Cont’d)
    21. 27. Long-term Safety of Co-treatments ???? <ul><li>Several cross-sectional and naturalistic studies reported an increased risk for diabetes 27 and cardiovascular mortality associated with antipsychotic polypharmacy . </li></ul><ul><li>However, it is unclear if these naturalistic findings are related to a direct toxic effect of specific or all antipsychotic combinations or whether it may be related to a cohort effect </li></ul>
    22. 28. Conclusion – I <ul><li>For severely ill patients with lack of response to antipsychotic monotherapy during the acute or chronic illness phase, antipsychotic cotreatment may be superior to antipsychotic monotherapy regarding all-cause discontinuation and general measures of efficacy. </li></ul><ul><li>Benefits apparent in acutely exacerbated patients in whom cotreatment is initiated at the beginning of treatment and when the cotreatment is administered for 10 weeks or more. </li></ul><ul><li>Moreover, benefits of antipsychotic cotreatment did not seem to be simply a function of an increase in antipsychotic dose and resultant dopamine blockade in the polytherapy group. </li></ul><ul><li>Clozapine is the most common used augment agent with FGA or SGA </li></ul><ul><li>Need to evaluate the potential short-term and, particularly, long-term risks of antipsychotic combinations are? </li></ul>
    23. 29. Conclsion - II <ul><li>Acc. to World Psychiatric </li></ul><ul><li>Association Pharmacopsychiatry the goal is to: </li></ul><ul><ul><li>achieve a maximum reduction of positive symptoms </li></ul></ul><ul><ul><li>Avoide EPS or the use of anticholinergic medication </li></ul></ul><ul><li>Probability of reaching this goal is more likely with SGA . </li></ul><ul><li>Younger age, inpatient treatment in the previous 12 months, as well as co-morbid disorders predicted polypharmacy at discharge </li></ul><ul><li>The newest guidelines in the survey recommended lower doses for first-episode patients </li></ul>Rune AK et al. BMC Psychiatry 2009, 9:24
    24. 30. Conclusion - III <ul><li>Use of Combination Therapy is too high </li></ul><ul><li>Patients are not getting adequate trials of monotherapy with atypical antipsychotics </li></ul><ul><li>Cross-tapering often leads to “psychopharmacology purgatory” </li></ul><ul><li>There is a need for a more structured approach to treatment with antipsychotic medications. </li></ul>