antipsychotics update

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  • 1. Antipsychotic drugs this decade (2002-2012) New Theories in AntipsychoticsPsychopharmacology

2. Aripiprasol (2002) Fazaclo (Sept, 14, 2005) Paliperidone (December 19, 2006) Illoperidone (May 7, 2009) Asenapine (August 15, 2009) Lurasidone (October 29, 2010) 3. Serotonin 5HT2A/dopamine D2RISPERIDONEantagonistILOPERIDONE-FDAapproved for acutetreatment ofschizophrenia inILOPERIDONE adults. 4. Efficacy comparable to other atypicals. Not approved for mania, but potentially effective. Has very low (placebo-level) EPS and little or noakathisia. Potent alpha 1 blocking properties suggestpotential utility in PTSD. Binding properties suggest theoretical efficacy indepression. Long half life suggests potential for once a daydosing. 5. Limited registration data and real world clinicalexperience; Slow titration Use caution with patients sensitive to orthostasis(young, elderly, CV problems) In presence of 2D6 inhibitors(paroxetine, fluvoxamine, duloxetine) reducedose by half Weight gain/metabolic profile comparable toRisperidone Dose-dependent QTc prolongation 6. SerotoninASENAPINE5HT2A/dopamine D2MIRTAZAPINE antagonistFDA approved for:-Acute and maintenancetreatment of schizophreniain adults,- Acute treatment of manicor mixed episodesassociated with bipolar 1disorder in adults 7. Mild metabolic risk; no prolactin elevation No dose titration needed Long half-life; once-daily dose is theoreticallypossible Sublingual tablet good for reliable, compliantpatient Not approved for depression, but binding profilesuggests potential use in treatment resistantcases 8. Not absorbed once swallowed; must beadministered sublingually Common side effect: oral hypoesthesia Patients may not eat or drink for 10 minutesafter administration to increase bioavailability Somnolence/sedation/EPS Inhibits 2D6 and is a substrate for 1A2 9. LURASIDONEFDA approved forschizophrenia in adults bothacute and maintenance.Lack of H1blockade suggests TANDOSPIRONE reduced risk of metabolicside effects and sedation.5HT7 antagonism may bebeneficial for cognitive andnegative symptoms. 10. Lack of affinity at H1 and M1receptors allowstreatment to begin at therapeutically effectivedose; rapid onset of action 40-80 mg/day effective for acuteexacerbation of schizophrenia Appears to have a benign metabolic profilewithout affecting QTc prolongation; low EPS Once-daily administration is possible 11. EPS and akathisia, but seems to be reduced iftaken at night. Will require confirmation from real worldclinical experience. 12. In order for an antipsychotic drug (typical or atypical) to beefficacious it has to occupy at least 60% of the D2 receptors. Receptor occupancy is a different concept than receptoraffinity. 13. Although standard doses of all antipsychotics target60-80% occupancy of D2 receptors, this may not besufficient to quell psychotic symptoms in all patients. Aggression associated with psychotic illness may stilloccur despite attaining 80% D2 receptor occupancywith standard doses of antipsychotics. In these cases higher doses of antipsychoticstargeting more than 80% D2 occupancy may bejustified, especially if effective in reducing assaultsand if side effects are carefully monitored. 14. Clozapine plasma levels of 350 450 ng/mlappears optimal. In refractory schizophrenia Clozapine cantitrated to a plasma level >450 ng/ml. Olanzapine blood levels 5-75 ng/ml In refractory cases can titrate to >125 ng/ml. Levels over 700-800 ng/ml cause QTcprolongation. 15. The old paradigm:Antipsychotic drugs are efficacious becausethey increase, decrease or alterthe neurotransmitters at synapses throughoutthe brain, thus correctingneurotransmission. 16. Antipsychotic drugs have immediate and lateeffects.Immediate effects include decrease ofdopamine in the brain dopaminergic tracts.Late effects are dendritic growth and BDNFsecretion leading to neuroprotection andneuroplasticity. 17. The new 21st century antipsychotic drugs willaim to: protect against gray matter loss, slow functional decline following the onset ofpsychosis, maintain functional integrity of the brain inresponse to neurobiological stress. 18. Some of the antipsychotics already in use areneuroprotective, such as Clozapine, Olanzapineand Aripiprasol Other neuroprotective agents being developed:- erythropoietin,- glycine,-D-serine,- neurosteroids,-memantine,-celecoxib 19. Astra Zeneca and GSK closed all their laboratories for mentalhealth research, including those the US, UK, Italy and elsewhere. Pfizer bought Pharmacia Upjohn and closed their CNS researchcenter in Kalamazoo, Michigan,than bought Parke Davis and closed their CNS research center inAnn Arbor, Michiganthan bought Wyeth and closed their CNS research center inPrinceton, NJ; andthen closed their own(Pfizer) CNS research center in the UK.Merck closed their CNS research center in the UK, then boughtOrganon/Schering Plough and closed their CNS research centerin the UK/Scotland.The list goes on and on. 20. Events that shaped the development ofantipsychotics this decade: 2003 Human Genome Project results werepublished. 2005 CATIE study results were published. 2009 Human Epigenome Project publishedresults. 2009 Human Connectome Project began. 21. What have we learned? Humans have around 20,000 genes Less than 1.5% of the genes codefor proteins. Genes account more for oursimilarities than for our differences. 22. Gene mining took the proportion of a gold rush.A gene for everything was envisioned. 23. Schizophrenia gene Bipolar gene Depression gene Anxiety gene 24. GENES DID NOT TELL US THE STORY WE WANTED TO HEAR 25. Human Genome did not evolve to validate DSM IVcriteria of mental illness. This raises serious questions about psychiatrictaxonomy. 26. There is no gene for schizophrenia, bipolar disorder, depressionor anxiety and there will never be one. Genes do not code for psychiatric illnesses or for symptoms ofpsychiatric illnesses. Genes operate at a very basic cellular level. They code formolecules and cells such as neuronal cytoskeleton, neuronalmigration proteins, myelin, cellular adhesion molecules, anddendritic cone growth. Genes do not respect the boundaries of psychiatric disorders. Forinstance most risk genes for schizophrenia are present also inbipolar disorder, schizoaffective disorder, Alzheimers diseaseand anxiety. Genes do not respect the boundaries of psychiatry, neurology ormedicine, etc. 27. Genes are nothing more than riskfactors for psychopathology.For instance schizophrenia risk genes code for:-Neuronal migration,-Neuronal differentiation,-Synaptogenesis,-Synaptic plasticity and-CytoskeletonGenes point to brain wiring. 28. How brains wire themselvesIt was said that studying mental disorderswithout connectomics is like researchinginfectious diseases without a microscope.This project:-Will elucidate the neural pathways thatunderlie brain function.-Will yield information about theconnectivity of each one of 150 billionneurons.A connectome is an axon with all of itsconnections. 29. Forest Gump would probably say: The brainis like a plate of spaghetti. 30. If it is not Nature can it be Nurture?Epigenome consists of chemical changes tothe DNA and histone proteins of a cell thatfacilitate or silence expression of genes. 31. Methylation keeps the histone proteins close together. In this statethe DNA cannot be transcribed the gene is not expressed. In order to be transcribed and expressed the histones must comeapart by either hypomethylation or acetilation. 32. The effectiveness of atypical antipsychoticsquestioned 33. Perphenazine, Olanzapine, Quetiapine, Risperidone and Ziprazidone were compared. Perphenazine was equally effective as theatypical antipsychotics and was as welltolerated as the newer drugs. The newer medications performed similarly toone another. 34. CATIE(Clinical Antipsychotic Trials ofIntervention Effectiveness) Patients assignedto Clozapine had the lowest discontinuationrate (56%), whileOlanzapine(71%), Risperidone(86%) andQuetiapine(93%). These data was confirmed by CUtLASS-2(CostUtility of the Latest Antipsychotic Drugs inSchizophrenia Study-brand 2) in England. 35. Search for neuroprotection 36. Direct-acting glycine agonists GlyT1 inhibitors(GRIs) 37. Phosphodiesterases (PDEs) are enzymes that degradecAMP and cGMP (involved in many second messengersystems). PDE 10A is concentrated in the striatum. PDE10A inhibitors lead to:-increased D1 receptor functioning-decreased D2 receptor functioningEffective for positive, negative and cognitivesymptoms 38. Reduced levels of alpha 7receptors in schizophrenia. Autosomal dominantpolymorphism of thealpha 7 gene on 15q14linked to cognitiveimpairments inschizophrenia. Alpha 7 agonists increasecortical dopamine and mayimprove cognitive andnegative symptoms. 39. Steven Stahl: "Case Studies: Stahls Essential Psychopharmacology" Cambridge, 2011, page 312. What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia. Schulte P. SourceMental Health Services North-Holland North, Heiloo, The Netherlands. Raphael.Schulte@wanadoonl Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophreniaresistant to conventional neuroleptics E. Spina, A. Avenoso, G. Facciol, M. G. Scordo, M. Ancione, A. G. Madia, A. Ventimiglia and E. Perucca What is an Adequate Trial with Clozapine?: Therapeutic Drug Monitoring and Time to Response in Treatment-Refractory Schizophrenia Author: Schulte, Peter F.J. Source: Clinical Pharmacokinetics, Volume 42, Number 7, 2003 , pp. 607-618(12) Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram Paul J. Perry AffiliationsDepartment of Psychiatry, College of Medicine (PJP, KAB, SA), University of Iowa, Iowa City, IowaUSADivision of Clinical


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