Antipsychotics: New agents and new perspectives on older agents

1. Antipsychotics: New agents and new perspectives on older agents Ted D. Williams PharmD, PGY1 Resident Syracuse VAMC June 9, 2010

2. Outline • Psychotic Disorders • Pathophysiology & Pharmacology • Typical vs. Atypical Antipsychotics • Side Effect Management • Therapy Management • A closer look at select agents

3. Psychosis vs. Neurosis • Psychosis • Inappropriate processing of sensory information • Disturbed views of reality and self • Not recognized by sufferer • Neurosis • Abnormal reactions • Recognized by sufferer by abnormal

4. Disorders with Psychotic Symptoms Possible • Big Three • Schizophrenia • Bipolar Disorder • Delirium in Dementia • Other Causes • Depression • Major Depressive Disorder • Secondary Depression • Post Traumatic Stress Disorder • Drug Induced

5. Schizophrenia Symptoms • Positive Symptoms • Disordered thoughts • Delusions • Paranoia • Hallucinations • Loose ideation • Negative Symptoms • Flat Affect • Anhedonia • loss of emotional response

6. Models of Psychosis • Current models suggest psychotic symptoms to be a disregulation in dopaminergicpathways • These models primary built on efficacy of dopamine antagonist in schizophrenia

7. Dopamine Receptor Response EPS Optimal Response • D2 receptor occupancy of 65%–70% correlates with maximal antipsychotic efficacy • unclear if this 65%–70% occupancy has to be continuously maintained or intermittently achieved (tight versus loose D2 receptor binding) • prolactin elevation appearing beyond 72% D2 occupancy • Extrapyramidal Symptoms (EPS) appear beyond 78% D2 occupancy without any increase in benefits at higher rates of occupancy Ineffective • Nasrallah, HA, Dandon, R.Textbook of Psychopharmacology:Chapter 27. Classic Antipsychotic Medications

8. Dopaminergic Pathways • Mesolimbic • Project from Ventral tegmental area to the cerebral cortex, including the Nucleus Accumbens (reward pathways) • Mesocortical • Project from Ventral tegmental area to the limbic structures • Tuberoinfundibular • D2 receptors in the Hypothalamus inhibit Prolactin secretion • Nigrostriatal pathway • Associated with Parkinsonian Symptoms

9. Pathology of Schizophrenia • Mesolimbic • Overactivity of mesolimbic pathway produce positive symptoms • Mesocortical • Underactivity of mesocortical pathways produces negative symptoms • Tuberoinfundibular and Nigrostriatal pathways unaffected by Schizophrenia MesolImbic Tuberoin-fundibular Nigrostriatal Meso-cortical

10. Typical vs. Atypical • Typical or First Generation Antipsychotics (FGA) have • High affinity for dopamine receptors • Low/no affinity for serotonin receptors • Atypical or Second Generation Antipsychotics (SGA) have • Moderate affinity for dopamine receptors • Increased affinity for serotonin Receptors

11. Rich Pharmacology is beneficial • FGA provide a strong dopama-lytic™response • SGA with 5-HT2 antagonism blocks normal vesicular release inhibition, promoting dopamine release into the synapse • This increased dopamine signal is believed to prevent downstream remodeling and development of EPS

12. Pharmacologic treatment of Schizophrenia • Dopamine blockade correct mesolimbic positive symptoms • Serotonin corrects mesocortical negative symptoms • Too much dopamine blockade causes • EPS via nigrostriatal • Lactation via Tuberoinfundibular • The models don’t entirely match clinical observations • Serotonin modeled to prevent tuberinfundibular and nigrostriatal symptoms • Clinical trial show FGA haloperidol to be more effective in improving negative symptoms than quetiapine MesolImbic MesolImbic Meso-cortical Tuberoin-fundibular Nigrostriatal Meso-cortical

13. Other Receptor Affinities • Alpha 1 Antagonism • Hypotension / Reflex Tachycardia • Sedation • Muscarinic Antagonists • Anticholinergic Effects • H1 Antagonism • Sedation • Weight Gain (Appetite)

14. Compilation of Receptor Affinities • FGA have high D2 affinity and low 5HT affinity • Newer SGA have balanced D2 and 5HT affinities

15. Pharmacology & Pathophysiology Summary • Dopamine antagonism is the primary proposed mechanism of psychosis • Multiple CNS pathways mediate symptoms and ADRs of agents • Synaptic dopamine levels appear to be modulated by serotonin • Achieving the correct level of synaptic dopamine is the key to therapeutic response without ADRs

16. Clinical Outcomes • Efficacy vs. Tolerability? • Both lack of efficacy and intolerability contribute significantly to very high discontinuation rates • Efficacy Measures • Psychiatric Scores • (e.g. PANSS, CGI) • Activities of Daily Living • Independent Living • Employment status • Tolerability • Weight Gain • EPS • Sedation • Lieberman, JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM 2005;353:1209-23.

17. Controversies • First vs. Second Generation Antipsychotics • Metabolic Side Effects

18. First vs. Second Generation • Leucht, S, Wahlbeck,K, Hamann,J, Kissling, W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. The Lancet, 2003:361;1581-1589 • Mean doses less than 600 mg/day of chlorpromazine or its equivalent had no higher risk of EPS than new generation drugs • Rosenheck, R, Perlick, D, Bingham, S. et al. Effectiveness and Cost of olanzapine and haloperidol in the treatment of schizophrenia: A randomized controlled trial. JAMA 2003;290:2693-2702. • n=309, 12 months, VA Study • Flexible dose olanzapine+benzotropine vs. flexible dose haloperidol • No significant differences in quality of life, symptoms, or ADR. • Olanzapine associated with significant metabolic syndrome and significantly higher costs $3,000-9,000 annually • Haloperidol associated with significant akathesia and reduced memory

19. First vs. Second Generation • Jones, PB, et al. Randomized controlled trial of the effect on quality of life of second vs. first generation antipsychotic drugs in schizophrenia. Archives of General Psychiatry 2006;63:1079-1087 • CUtLASS 1 trial. • n=275, 52 weeks randomized to FGA or SGA for patient who failed antipsychotic therapy (ineffective or ADR) • Quality of Life Scale and psychotic symptom scores not significantly different between groups • The debate rages on, but the pendulum appears to be swinging back towards the re-introductions of FGA

20. Metabolic side effects • Metabolic Alterations • Weight • Glucose • Lipids • Lipid panel required every 6 months for all antipsychotics per VA/DoD Guidelines • Proposed Mechanisms • H1, serotonin, and alpha-1 antagonism have all been suggested • Appetite stimulation • Insulin resistance

21. Clinical Comparison of Weight Gain • CATIE Trial • Greater than 7% increase in body weight • (p < 0.001) • Olanzapine 30% • Quetiapine 16% • Risperidone 14% • Perphenazine 12% • Ziprasidone 7%

22. Treatment of Metabolic Syndrome • Exercise!!!! • Increase insulin sensitivity • Controls weight • Diet • Weight gain partially due to appetite stimulation • Metformin • Increase insulin sensitivity • Reduces appetite (GI ADRs) • Topiramate • Taste perversion • HealthBuddy™? • Ellinger, LK, Ipema, HJ, Stachnik,JM. Efficacy of Metformin and Topiramate in Prevention and Treatment of Second-Generation Antipsychotic–Induced Weight Gain. Annals of Pharmacotherapy 2010;44:668-79. • Bushe, CJ, Bradley, AJ, Doshi, S, Karagianis, J. Changes in weight and metabolic parameters during treatment with antipsychotics and metformin: do thedata inform as to potential guideline development? A systematic review of clinical studies. The International Journal of Clinical Practice. 2009 • Wong, R-R, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naïve first-episode schizophrenia aptients: A double-blind, placebo-controlled study. AmericanJournal of Psychiatry 2008; 165:352–358

23. Monitoring of Metabolic Side Effects of Antipsychotics • Morrato, EH et al. Metabolic screening after the American Diabetes Association’s consensus statement on antipsychotic drugs and diabetes. Diabetes Care 2009;32:1037-1042

24. EPS • Extra Pyramidal Side Effects • Generated by extra pyramidal cells in the nigrostriatal pathway • Range from lip smacking to gross tremors • Abnormal Involuntary Movements Scale (AIMS) • 12 item clincician administered test • Four questions on orofacialmovments • Three questions on extremity and truncaldyskinesia • 3 questions on global severity, both patient and clinician perspectives • Two questions about possible dental confounders • Should be re-administered at least every 6 months for antipsychotics to be re-approved • Available for download at http://www.cqaimh.org/pdf/tool_aims.pdf • Treatment/Prevention • Anticholinergics • Diphenhydramine • Benztropine

25. ADR Management Summary • Antipsychotic therapy has a very high failure rate due to both intolerance and lack of efficacy • EPS have classically been associated with FGA, but that may have been a dose-response effect • Metabolic side effects are know, but not typically well managed in the community • Nothing but opportunity for pharmacist to help manage therapy

26. Therapy Management

27. Polypharmacy: Is it good policy? • Rational • No studies have been performed demonstrating multiple antipsychotics to be more effective than monotherapy • Clinically Appropriate • Antipsychotics have a high discontinuation rate • There is a documented efficacy hierarchy, with Olanzapine and Clozapine having been demonstrated to be the most efficacious in refractory schizophrenia • Safe • Current models of schizophrenia as a D2 mediated disorder suggest that multiple agents with the same MOA is essentially administering supra-maximal doses • Cost Effective • Principles of a Sound Drug Formulary System.  October 2000 • Lieberman, JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM 2005;353:1209-23

28. Cross Tapering – When polypharmacy make sense • Comparison of three switching strategies • RR of early discontinuation was 0.77 (CI 0.61–0.99) • Can discontinuation of previous antipsychotic be part of the non-formulary approval process? • Ganguli, R. et al. Assessment of strategies for switching patients from olanzapine to risperidone: A randomized, open-label, rater-blinded study. Medicine 2008, 6:17

29. Formulary Recommendations Risperidone Quetiapine • Each agent should undergo a 6 week trial for efficacy • AIMS testing and lipid screening is required with ALL SGA at initiation and every 6 months. Aripiprazole Ziprasidone Candidate for Clozapine No Yes Clozapine Olanzapine Paliperidone

30. Equipotent Dosing *Haloperidol equivalent dose is 3 mg at<20 mg/d and 5 mg at >20 mg/d • Woods, Chlorpromazine equivalent doses for the newer atypical antipsychotics.Journal of Clinical Psychiatry. 2003;64:663-667 • Atkins, M, Burgess, A, Bottmley, C, Riccio, M. Chlorpromazine equivalents: a consensus of opinion for both clinical and research applications. Psychiatric Bulletin 1997;21:224-226 • Pricing from VISN 2 CPRS. Retrieved 6/8/2010

31. Clozapine • Widely regarded as the most effective SGA • Avoided because of agranulocytosis • Occurs in less than 2% of patients • Typically within the first 6 months • Requires weekly monitoring • WBC >2000/mm3 • ANC >1000/mm3 • Also has significant, dose-response weight gain, approximately one pound per week • Providers at the Syracuse VA recognize it can be tremendously effective, but are reluctant to use it due to intensive monitoring and workload constraints • What a great opportunity for pharmacy!!! • Agid, O. et al. Early Use of Clozapine for Poorly Responding First-Episode Psychosis Journal of Clinical Psychopharmacology 2007;27:369-373 • Clozapine Underutilization and Discontinuation in African Americans Due to Leucopenia Schizophrenia Bulletin 2007;33:1221–1224 • deLeon, J. et al. Weight Gain During a Double-Blind Multidosage Clozapine Study Journal of Clinical Psychopharmacology 2007;27:22-27 • McEvoy et al. Effectiveness of Clozapine Versus Olanzapine,Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical\Antipsychotic Treatment Am J Psychiatry 2006; 163:600–610 • Alvir, JMJ, et al. Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States. NEJM 1993’;329:162-167

32. Non-Traditional Uses • PTSD • Olanzapine and Risperidone have been demonstrated no more effective than placebo in controlling symptoms • Depression • Antipsychotics as add on therapy, not as monotherapy in PSYCHOTIC depression vs. Major Depressive Disorder may be appropriate. • Monotherapy is less effective than SSRI based therapy • Insomnia • Primarily due to anticholinergic effects • Can you say hydroxyzine? • Per VISN 2 formulary: Please try to deter providers from using low-dose quetiapine 25mg QHS for sleep. • Agitation • Some have FDA indication for this use • Olanzapine IM • Aripiprazole IM • Ziprasidone IM • Stein, DJ, Ipser, JC, Seedat, S. Pharmacotherapy for post traumatic stress disorder (PTSD). The Cochrane Collaborative. 2009 • Wijkstra, J, Lijmer, J, Blak, F, Geeddes, J, Nlen, WA. Pharmacological treatment for psychotic depression. The Cochrane Collaborative. 2009

33. Agitation & Behavioral Emergencies • The Expert Consensus Guideline Series. Treatment of Behavioral Emergencies 2005. J PsychiatrPract. 2005;11 Suppl 1:5-108 • No SGA emerges as a non-specific replacement for haloperidol. • If using haloperidol, use with benzodiazepines • For oral treatment for agitation related to schizophrenia or mania first line is • Haloperidol plus Benzodiazepines • Risperidone +/- Benzodiazepines • Olanzapine +/- Benzodiazepines • Second line therapy • Ziprasidone • Quetiapine

34. New Agents • Asenapine (Saphris®) • Dibenzamine, similar to olanzapine and clozapine • Low Muscarinic receptor affinity • High Dopamine and serotonin affinities • Available only as a sublingual formulation • Iloperidone(Fanapt®) • Structurally similar to risperidone and aripiprazole • Low muscarinic receptor affinity • High affinity for dopamine and serotonin receptors • Also as norepinephrine receptor affinity • Available as standard tablets • No significantly compelling reasons to add to the formulary • Descriptive information from Clinical Pharmacology Online Database • Structures downloaded from wikipedia.org

35. Therapy Management Summary • Polypharmacy is not justified by • Mechanistic benefits • Evidence based medicine • Cost • Treatment resistant patient should work through the formulary, giving serious consideration to pharmacist-assisted use of clozapine • Gradual cross titration of antipsychotics is appropriate, but pharmacist should monitor carefully to prevent inadvertent polypharmacy • SGA not demonstrated superior to haloperidol + BNZ for agitation • Newest agents are, in essence, “me-too” agents and are not easily justified clinically or economically

36. Conclusions • Antipsychotic therapy is a moving target, with a shifting debate on optimal therapy • Therapy management consists of carefully, continuous, and deliberately balancing efficacy and side effects • To date, poly-pharmacy (2+antipsychotics) is not rational, safe, cost-effective • The formulary actually does a good job of balancing efficacy and ADRs • The opportunities for pharmacist to optimize therapy are HUGE