ANTIPSYCHOTIC MEDICATIONS SHORT 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)

FDA Approved Antipsychotics This Decade

Iloperidone (Fanapt)

RISPERIDONE

ILOPERIDONE

Serotonin 5HT2A/dopamine D2 antagonist

ILOPERIDONE-FDA approved for acute treatment of schizophrenia in 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.

Iloperidone

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

Iloperidone

Asenapine (Saphris)

MIRTAZAPINEASENAPINE

Serotonin 5HT2A/dopamine D2 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

Asenapine

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

Asenapine

Lurasidone (Latuda)

LURASIDONE

TANDOSPIRONE

FDA approved for schizophrenia in adults both acute and maintenance.

Lack of H1blockade suggests 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

Lurasidone

EPS and akathisia, but seems to be reduced if taken at night.

Will require confirmation from real world clinical experience.

Lurasidone

When Antipsychotics Are Ineffective

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.

Effectiveness Proportional With D2 Receptor Occupancy

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.

Antipsychotics at High Doses

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.

Plasma Levels in Refractory Cases

This Decade a Paradigm Shift Occurred In the Psychopharmacology of Antipsychotic Drugs

The old paradigm:

Antipsychotic drugs are efficacious because they increase, decrease or alter

the neurotransmitters at synapses throughout the brain, thus correcting

neurotransmission.

Conventional Theory of Psychopharmacology is Changing

Antipsychotic drugs have immediate and late effects.

Immediate effects include decrease of dopamine in the brain dopaminergic tracts.

Late effects are dendritic growth and BDNF secretion leading to neuroprotection and

neuroplasticity.

The New Paradigm

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.

Neuroprotective Antipsychotics

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

Neuroprotective Agents In Schizophrenia

Follow The Pharma Money Trail

Astra Zeneca and GSK closed all their laboratories for mental health research, including those the US, UK, Italy and elsewhere.

Pfizer bought Pharmacia Upjohn and closed their CNS research center in Kalamazoo, Michigan,

than bought Parke Davis and closed their CNS research center in Ann Arbor, Michigan

than bought Wyeth and closed their CNS research center in Princeton, NJ; and

then closed their own(Pfizer) CNS research center in the UK.

Merck closed their CNS research center in the UK, then bought Organon/Schering Plough and closed their CNS research center in the UK/Scotland.

The list goes on and on.

Paradigm Shift Reflected in The Industry

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.

Events that Contributed to Paradigm Shift

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.

Human Genome Project Was Completed in 2003

Gene mining took the proportion of a “gold rush.”

A gene for everything was envisioned.

In The Beginning - Enthusiasm

Schizophrenia gene Bipolar gene Depression gene Anxiety gene

Genes Became The Holy Grail of Psychiatry

GENES DID NOT TELL US THE STORY WE WANTED TO HEAR

Era of Disappointment With the Genes

Human Genome did not evolve to validate DSM IV criteria of mental illness.

This raises serious questions about psychiatric taxonomy.

The Inconvenient Truth

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 Do not Cause Psychiatric Illness

Genes are nothing more than riskfactors for psychopathology.For instance schizophrenia risk genes code

for:-Neuronal migration,-Neuronal differentiation, -Synaptogenesis, -Synaptic plasticity and-Cytoskeleton

Genes point to brain wiring.

Did Psychiatry Learn Anything From the Genes?

How brains wire themselves

It was said that studying mental disorders without connectomics is like researching infectious diseases without a microscope.

This project:-Will elucidate the neural pathways that underlie brain function.

-Will yield information about the connectivity of each one of 150 billion neurons.

A connectome is an axon with all of its connections.

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

The Connectome

Genes and Environment

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.

The Epigenom Depends on the Environment

Epigenetics: Genes and Environment

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.

Methylation of Histone Proteins Prevents Gene Expression

The effectiveness of atypical antipsychotics questioned

Perphenazine, Olanzapine, Quetiapine, Risperidone 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.

All Antipsychotics Have Similar Effectiveness

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.

Discontinuation Rates

Dopamine Spectrum

Search for neuroprotection

The Future of Antipsychotics

Direct-acting glycine agonists GlyT1 inhibitors(GRIs)

Modulation of Glutamatergic Transmission

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 functioning

Effective for positive, negative and cognitivesymptoms

Phosphodiesterase 10A Inhibitors

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.

Nicotinic Alpha 7 Agonists

Steven Stahl: "Case Studies: Stahl's 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.        

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