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Download  Psychotic Disorders  Pathophysiology & Pharmacology  Typical vs. Atypical Antipsychotics  Side Effect Management  Therapy Management  A closer

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  • Psychotic Disorders Pathophysiology & Pharmacology Typical vs. Atypical Antipsychotics Side Effect Management Therapy Management A closer look at select agents
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  • Psychosis Inappropriate processing of sensory information Disturbed views of reality and self Not recognized by sufferer Neurosis Abnormal reactions Recognized by sufferer by abnormal
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  • Big Three Schizophrenia Bipolar Disorder Delirium in Dementia Other Causes Depression Major Depressive Disorder Secondary Depression Post Traumatic Stress Disorder Drug Induced
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  • Positive Symptoms Disordered thoughts Delusions Paranoia Hallucinations Loose ideation Negative Symptoms Flat Affect Anhedonia loss of emotional response
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  • Current models suggest psychotic symptoms to be a disregulation in dopaminergic pathways These models primary built on efficacy of dopamine antagonist in schizophrenia
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  • 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
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  • 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
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  • 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
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  • 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
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  • FGA provide a strong dopama-lyticresponse 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
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  • 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 dont 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
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  • Alpha 1 Antagonism Hypotension / Reflex Tachycardia Sedation Muscarinic Antagonists Anticholinergic Effects H1 Antagonism Sedation Weight Gain (Appetite)
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  • FGA have high D2 affinity and low 5HT affinity Newer SGA have balanced D2 and 5HT affinities
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  • 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
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  • 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.
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  • First vs. Second Generation Antipsychotics Metabolic Side Effects
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  • 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
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  • 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
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  • 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
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  • CATIE Trial Greater than 7% increase in body weight (p < 0.001) Olanzapine 30% Quetiapine 16% Risperidone 14% Perphenazine 12% Ziprasidone 7%
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  • 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 AntipsychoticInduced 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-nave first-episode schizophrenia aptients: A double-blind, placebo-controlled study. American Journal of Psychiatry 2008; 165:352358
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  • Morrato, EH et al. Metabolic screening after the American Diabetes Associations consensus statement on antipsychotic drugs and diabetes. Diabetes Care 2009;32:1037-1042
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  • 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
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  • 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
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  • 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
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  • Comparison o

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