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

4.  Psychosis › Inappropriate processing of sensory information › Disturbed views of reality and self › Not recognized by sufferer  Neurosis › Abnormal reactions › Recognized by sufferer by abnormal

5.  Big Three › Schizophrenia › Bipolar Disorder › Delirium in Dementia  Other Causes › Depression  Major Depressive Disorder  Secondary Depression › Post Traumatic Stress Disorder › Drug Induced

6.  Positive Symptoms › Disordered thoughts › Delusions › Paranoia › Hallucinations › Loose ideation  Negative Symptoms › Flat Affect › Anhedonia  loss of emotional response

7.  Current models suggest psychotic symptoms to be a disregulation in dopaminergic pathways  These models primary built on efficacy of dopamine antagonist in schizophrenia

8.  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 EPS Optimal Response Nasrallah, HA, Dandon, R.Textbook of Psychopharmacology:Chapter 27. Classic Antipsychotic Medications

9.  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

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

11.  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

12.  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

13. Meso- cortical MesolImbic  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 Tuberoin- fundibular Nigrostriatal MesolImbic

14.  Alpha 1 Antagonism › Hypotension / Reflex Tachycardia › Sedation  Muscarinic Antagonists › Anticholinergic Effects  H1 Antagonism › Sedation › Weight Gain (Appetite)

15.  FGA have high D2 affinity and low 5HT affinity  Newer SGA have balanced D2 and 5HT affinities

16.  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

17.  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.

18.  First vs. Second Generation Antipsychotics  Metabolic Side Effects

19.  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

20.  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

21.  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

22.  CATIE Trial › Greater than 7% increase in body weight › (p < 0.001) › Olanzapine 30% › Quetiapine 16% › Risperidone 14% › Perphenazine 12% › Ziprasidone 7%

23.  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. American Journal of Psychiatry 2008; 165:352–358

24.  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

25.  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 orofacial movments  Three questions on extremity and truncal dyskinesia  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.pdfhttp://www.cqaimh.org/pdf/tool_aims.pdf  Treatment/Prevention › Anticholinergics  Diphenhydramine  Benztropine

26.  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

28. 1. Rational › No studies have been performed demonstrating multiple antipsychotics to be more effective than monotherapy 2. 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 3. Safe › Current models of schizophrenia as a D2 mediated disorder suggest that multiple agents with the same MOA is essentially administering supra-maximal doses 4. 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

29.  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

30.  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. Risperidone Quetiapine Risperidone Quetiapine Aripiprazole Ziprasidone Aripiprazole Ziprasidone Candidate for Clozapine Candidate for Clozapine No Clozapine Olanzapine Paliperidone Yes

31. MedicationChlorpromazine 100mg/day equivalents (mg) Typical dosage range (mg) VA cost based on maximum daily dose Clozapine50250-500$3 Quetiapine75300-800$6 Olanzapine515-30$22 Ziprasidone6080-160$8 Risperidone22-6$1 Aripiprazole7.510-30$6 Haloperidol3*~15$0.37 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 *Haloperidol equivalent dose is 3 mg at 20 mg/d

32.  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

33.  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

34.  The Expert Consensus Guideline Series. Treatment of Behavioral Emergencies 2005. J Psychiatr Pract. 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

35.  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

36.  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

37.  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