Antipsychotics update

Antipsychotic drugs this decade (2002-2012) New Theories in Antipsychotics’ Psychopharmacology

 Aripiprasol (2002) Fazaclo (Sept, 14, 2005) Paliperidone (December 19, 2006) Illoperidone (May 7, 2009) Asenapine (August 15, 2009) Lurasidone (October 29, 2010)

Serotonin 5HT2A/dopamine D2RISPERIDONE antagonist ILOPERIDONE-FDA approved for acute treatment of schizophrenia in ILOPERIDONE adults.

 Efficacy comparable to other atypicals. Not approved for mania, but potentially effective. Has very low (placebo-level) EPS and little or no akathisia. Potent alpha 1 blocking properties suggest potential utility in PTSD. Binding properties suggest theoretical efficacy in depression. Long half life suggests potential for once a day dosing.

 Limited registration data and real world clinical experience; Slow titration Use caution with patients sensitive to orthostasis (young, elderly, CV problems) In presence of 2D6 inhibitors (paroxetine, fluvoxamine, duloxetine) reduce dose by half Weight gain/metabolic profile comparable to Risperidone Dose-dependent QTc prolongation

SerotoninASENAPINE 5HT2A/dopamine D2 MIRTAZAPINE antagonist FDA approved for: -Acute and maintenance treatment of schizophrenia in adults, - Acute treatment of manic or mixed episodes associated with bipolar 1 disorder in adults

 Mild metabolic risk; no prolactin elevation No dose titration needed Long half-life; once-daily dose is theoretically possible Sublingual tablet good for reliable, compliant patient Not approved for depression, but binding profile suggests potential use in treatment resistant cases

 Not absorbed once swallowed; must be administered sublingually Common side effect: oral hypoesthesia Patients may not eat or drink for 10 minutes after administration to increase bioavailability Somnolence/sedation/EPS Inhibits 2D6 and is a substrate for 1A2

LURASIDONE FDA approved for schizophrenia in adults both acute and maintenance. Lack of H1blockade suggests TANDOSPIRONE reduced risk of metabolic side effects and sedation. 5HT7 antagonism may be beneficial for cognitive and negative symptoms.

 Lack of affinity at H1 and M1receptors allows treatment to begin at therapeutically effective dose; rapid onset of action 40-80 mg/day effective for acute exacerbation of schizophrenia Appears to have a benign metabolic profile without affecting QTc prolongation; low EPS Once-daily administration is possible

 EPS and akathisia, but seems to be reduced if taken at night. Will require confirmation from real world clinical experience.

 In order for an antipsychotic drug (typical or atypical) to be efficacious it has to occupy at least 60% of the D2 receptors. Receptor occupancy is a different concept than receptor affinity.

 Although standard doses of all antipsychotics target 60-80% occupancy of D2 receptors, this may not be sufficient to quell psychotic symptoms in all patients. Aggression associated with psychotic illness may still occur despite attaining 80% D2 receptor occupancy with standard doses of antipsychotics. In these cases higher doses of antipsychotics targeting more than 80% D2 occupancy may be justified, especially if effective in reducing assaults and if side effects are carefully monitored.

 Clozapine plasma levels of 350 – 450 ng/ml appears optimal. In refractory schizophrenia Clozapine can titrated 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 QTc prolongation.

The old paradigm:Antipsychotic drugs are efficacious becausethey increase, decrease or alterthe neurotransmitters at synapses throughoutthe brain, thus correctingneurotransmission.

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.

The new 21st century antipsychotic drugs willaim to: protect against gray matter loss, slow functional decline following the onset of psychosis, maintain functional integrity of the brain in response to neurobiological stress.

 Some of the antipsychotics already in use are neuroprotective, such as Clozapine, Olanzapine and Aripiprasol Other neuroprotective agents being developed:- erythropoietin,- glycine,-D-serine,- neurosteroids,-memantine,-celecoxib

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.

Events that shaped the development ofantipsychotics this decade: 2003 Human Genome Project results were published. 2005 CATIE study results were published. 2009 Human Epigenome Project published results. 2009 Human Connectome Project began.

What have we learned? Humans have around 20,000 genes Less than 1.5% of the genes code for proteins. Genes account more for our similarities than for our differences.

Gene mining took the proportion of a “gold rush.”A gene for everything was envisioned.

 Schizophrenia gene Bipolar gene Depression gene Anxiety gene

 GENES DID NOT TELL US THE STORY WE WANTED TO HEAR

 Human Genome did not evolve to validate DSM IV criteria of mental illness. This raises serious questions about psychiatric taxonomy.

There is no gene for schizophrenia, bipolar disorder, depression or anxiety and there will never be one. Genes do not code for psychiatric illnesses or for symptoms of psychiatric illnesses. Genes operate at a very basic cellular level. They code for molecules and cells such as neuronal cytoskeleton, neuronal migration proteins, myelin, cellular adhesion molecules, and dendritic cone growth. Genes do not respect the boundaries of psychiatric disorders. For instance most risk genes for schizophrenia are present also in bipolar disorder, schizoaffective disorder, Alzheimer’s disease and anxiety. Genes do not respect the boundaries of psychiatry, neurology or medicine, etc.

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.

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.

 Forest Gump would probably say: “The brain is like a plate of spaghetti”.

 If it is not Nature can it be Nurture? Epigenome consists of chemical changes to the DNA and histone proteins of a cell that facilitate or silence expression of genes.

 Methylation keeps the histone proteins close together. In this state the DNA cannot be transcribed – the gene is not expressed. In order to be transcribed and expressed the histones must come apart by either hypomethylation or acetilation.

 The effectiveness of atypical antipsychotics questioned

 Perphenazine, Olanzapine, Quetiapine, Risper idone and Ziprazidone were compared. Perphenazine was equally effective as the atypical antipsychotics and was as well tolerated as the newer drugs. The newer medications performed similarly to one another.

 CATIE(Clinical Antipsychotic Trials of Intervention Effectiveness) – Patients assigned to Clozapine had the lowest discontinuation rate (56%), while Olanzapine(71%), Risperidone(86%) and Quetiapine(93%). These data was confirmed by CUtLASS-2(Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study-brand 2) in England.

 Search for neuroprotection

 Direct-acting glycine agonists GlyT1 inhibitors(GRIs)

 Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP (involved in many second messenger systems). PDE 10A is concentrated in the striatum. PDE10A inhibitors lead to:-increased D1 receptor functioning-decreased D2 receptor functioningEffective for positive, negative and cognitivesymptoms

 Reduced levels of alpha 7 receptors in schizophrenia. Autosomal dominant polymorphism of the alpha 7 gene on 15q14 linked to cognitive impairments in schizophrenia. Alpha 7 agonists increase cortical dopamine and may improve cognitive and negative symptoms.

 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 schizophrenia resistant to conventional neuroleptics E. Spina, A. Avenoso, G. Facciolà, 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 Pharmacy, College of Pharmacy (PJP, MDC), University of Iowa, Iowa City, IowaUSAAddress reprint requests to Paul J. Perry, PhD, S-415 Pharmacy Bldg, College of Pharmacy, University of Iowa, Iowa City, IA 52242 , Kristine A. Bever AffiliationsDepartment of Psychiatry, College of Medicine (PJP, KAB, SA), University of Iowa, Iowa City, IowaUSA , Stephan Arndt AffiliationsDepartment of Psychiatry, College of Medicine (PJP, KAB, SA), University of Iowa, Iowa City, IowaUSA , Michael D. Combs AffiliationsDivision of Clinical Pharmacy, College of Pharmacy (PJP, MDC), University of Iowa, Iowa City, IowaUSA Received 28 July 1997; received in revised form 30 October 1997; accepted 14 November 1997.

Antipsychotics update

by Adonis Sfera, MD

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