Psychosis and AntipsychoticsADONIS SFERA, MD

Psychosis definition, biological markers, FDA approved antipsychotics this decade, computation model in psychosis, psychosis/antipsychotics and brain tissue loss, patient specific cultured neurons

What Makes an Antipsychotic Conventional?

D2 Antagonist Actions

D2

5HT2A

D2

-D2 antagonist action-5HT2A antagonist action

What Makes an Antipsychotic Atypical?

D2 Blockade

D2 and 5HT2A Blockade

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

21st Century Psychiatry

Events that Shaped the Development ofAntipsychotics this Decade:

2003 Human Genome Project results were published.

2009 Human Epigenome Project published results.

2009 Human Connectome Project began.

Novel neuroimaging Techniques Discovery of the Ultramicrotome

From Freud to Prozac

The Brain as a Black BoxUpbringing determines the output

19th and early 20th century paradigm

Biochemical ParadigmFrom blaming the mother to blaming neurotransmitters

Second half of the 20th century 1954 discovery of Chlorpromazine Psychopharmacology The biochemical trinity: -dopamine -serotonin - norepinephrine

Computational Paradigm Putting Brains Back in Psychiatry

Computation: Information Processing -

Brain is the hardware, mind is the software

Advances in microscopy and imaging: 150 billion neurons Each neuron up to 900 synapses Number of connections - trillions Connections organized in hubs and networks

Large Brain Networks

Large Scale Brain Networks in Cognition, emerging methods and principles;Steven Bresler, Vinod Menon;Trends in cognitive science, Vol 14,June 2010, pages277-290;http://dx.doi.org/10.1016/j.tics2010 .04.004

The salience network initiates dynamic switching between the central-executive and default-mode networks, and mediates between attention to endogenous and exogenous events.

Advances in Functional MRI fMRI revealed: the brain to be a highly connected

organ

Advantages & Disadvantages of fMRI

In vivo(can see the brain at work)

The resolution of fMRI is 1 mm

1000 neurons per mm of gray matter

Regional connectomics

Automated Tape-Collecting Ultramicrotome (ATUM)

Cellular Connectomics

Connectomics in Schizophrenia

Bullmore&Sporns, Nat Rev Neuroscii 2009

Schizophrenia : fronto-temporal dysconnectivity Graph Analysiss

Nodes= small , large or average clustering

healthy subjects

schizophrenia patients

Psychosis

Causes of Psychosis Tumors: temporal lobe (auditory), occipital lobe (visual), limbic and hypothalamus (delusions) Seizures: temporal lobe, grand-mal (post-ictal psychosis) Parkinson’s disease: secondary to mood disorders, dementia or antiparkinsonian drugs Huntington’s disease Multiple Sclerosis Amyotrophic lateral sclerosis Neurosyphilis Meningitis/encephalitis HIV Hypo/hyperthyroidism Hypo/hyper parathyroidism Adrenal disorders (Addison’s or Cushing’s disease) Systemic Lupus erythematosus Sodium/potassium inbalance Hepathic encephalopathy Uremic encephalopaty Acute intermittent porphyria Vitamin B12 or folate deficiency Heavy metal poisoniong Wilson’s disease Dialysis

Psychosis and Substances

Amphetamines, hallucinogens or cannabis Corticosteroid treatment Alcohol intake Dopaminergic drugs (L-dopa, Amantadine) Interferon Anticholinergics Cardiovascular drugs Anesthetics Antimalarial drugs Antituberculous drugs: d-cycloserine, ethambutol, isoniasid Antibiotics: cprofloxacin Antivirals: HIV medications (efavirenz, acyclovir) Antineoplasic drugs Sympatomimetics Pain medications (meperidine, pentazocine, indomethacin)

Psychosis – A Brain Arrhythmia?

Default mode of information processing to which the brain resorts under stress.

The amount of stress necessary to activate psychotic information processing mode depends on the cerebral reserve.

Brain's Default Mode Network The brain's default mode network -- a series of connected

areas that work hardest when most of the brain is at rest Two major hubs: -posterior cingulate cortex with the precuneus -medial prefrontal cortex

Brain’s “Default Mode” Awry in Schizophrenia

American Journal of Psychiatry 164: 450-457 (March 2007)

Newest Antipsychotics Advantages

Iloperidone (Fanapt) Asenapine Lurasidone

Efficacy comparable to other atypicals

Mild metabolic risk; no prolactin elevation

Lack of affinity at H1 and M1receptors allows treatment to begin at therapeutically effective dose; rapid onset of action

Not approved for mania, but potentially effective.

No dose titration needed 40-80 mg/day effective for acute exacerbation of schizophrenia

Has very low (placebo-level) EPS and little or no akathisia

Long half-life; once-daily dose is theoretically possible

Appears to have a benign metabolic profile without affecting QTc prolongation; low EPS

Potent alpha 1 blocking properties suggest potential utility in PTSD

Sublingual tablet good for reliable, compliant patient

Once-daily administration is possible

Binding properties suggest theoretical efficacy in depression

Not approved for depression, but binding profile suggests potential use in treatment resistant cases

Newest Antipsychotics Disadvantages

Iloperidone Asenapine Lurasidone

Dose-dependent QTc prolongation

Not absorbed once swallowed; must be administered sublingually

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

Slow titration Common side effect: oral hypoesthesia

Will require confirmation from real world clinical experience

Use caution with patients sensitive to orthostasis (young, elderly, CV problems)

Patients may not eat or drink for 10 minutes after administration to increase bioavailability

In presence of 2D6 inhibitors (paroxetine, fluvoxamine, duloxetine) reduce dose by half

Somnolence/sedation/EPS

Weight gain/metabolic profile comparable to Risperidone

Inhibits 2D6 and is a substrate for 1A2

FDA Indications

Iloperidone Dosing

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

1 mg BID

2 mg BID

4 mg BID

6 mg BID

8 mg BID

10 mg BID

12 mg BID

Iloperidone -Tolerability Moderate effects on body weight-Iloperidone-induced changes in weight are independent from

significant changes in glucose or lipid levels

Low rate akathisia

Slow titration and careful monitoring of orthostatic hypotension are required

-Especially in the elderly or when used in combination with other medications that may induce orthostasis (e.g., diuretics, TCA)

Significant risk of QTc prolongation

Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

Asenapine DosingSublingual Formulation-bioavailability when swallowed is very low-avoid eating or drinking for 10 min after administration

Typical dose-Schizophrenia 5 mg BID-Bipolar mania 10 mg BID

May be useful as a rapid-acting PRN antipsychotic

No dose adjustment necessary in patients with moderate hepatic or renal impairment

Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

Asenapine TolerabilityLimited effects on weight-small, non-significant effects on fasting glucose levels have been observed-no clinically significant effects on total cholesterol or fasting triglycerides have

been observed

Slightly elevated risk of akathisia and EPS

Oral hypoesthesia and somnolence are not uncommon

May induce orthostatic hypotension and syncope

Marginal effects on QTc interval

Benign effects on prolactin.

Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

Lurasidone DosingRecommended starting dose 40 mg/dayMaximum recommendined dose was originally80 mg/day, now 160.-In May 2012 FDA approved an extended dose range of 40-160 mg/day for

schizophrenia-120 mg tablet currently in development

No titration required

Should be taken with food (at least 350 calories)

Should not exceed 40 mg/day in patients withmoderate to severe renal or hepatic impairment.

Lurasidone TolerabilityBenign metabolic profile-minimal changes in body weight-no significant changes in total cholesterol, triglycerides, LDLs,

HDLs or fasting glucose

Risk of akathisia at higher doses

No QTc prolongation

Small increase in in prolactine

Administering Lurasidone at night may reduce side-effects

CariprazineD2 partial agonist-more of an antagonist than AripiprazoleIn late stage clinical testing for schizophrenia, acute bipolar

mania, bipolar depression and treatment resistant depression-higher doses for schizophrenia and mania (antagonist actions)-lower doses for depression (agonist action)

Stronger affinity for D3 than D2 receptors

Few metabolic side effects and low risk for EPS

Long lasting metabolite.

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Brexpiprazole

D2 partial agonist-more of an antagonist than Aripiprazole

Very low risk for EPS and rare akathisia so far despite strong affinity for D2 receptors

-possibly due to potent 5HT2A antagonism, 5HT1A antagonism and alpha 1 antagonism

Potential treatment for agitation and psychosis in dementia

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4 th ed 2011

Glutamate in Schizophrenia NMDA hypofunction hypothesis of

schizophrenia

Neurodevelopmentally abnormal glutamate synapses

Hypofunctional NMDA receptors

Modulation of glutamatergic transmission as a potential treatment strategy

-direct acting glycine agonists-mGluR 2/3 presinaptic agonist-GlyT1 inhibitors (SGRIs)

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

The trouble with the world is not that people know too little, is that they know so many things that just aren’t so Mark Twain

Both Psychosis and Some Antipsychotics Cause Brain Tissue Loss

Brain Changes Associated with Antipsychotics

Typical antipsychotics: enlargement of the putamen reduction of lobulus paracentralis,

anterior cingulate gyrus, superior and medial frontal gyri, superior and middle temporal gyri, insula and precuneus).

Atypical antipsychotics:enlargement of the thalami.

Atypical Antipsychotics Promote Neurogenesis

NGF, BDNF,GDNF, fibroblast growth factors (FGF)are decreased by 60% in first episode psychosis (FEP).

Over two dosed studies showed that atypical antipsychotics increase growth factors, stimulate neurite extension, neurogenesis and cell survival

Typical antipsychotics lower BDNF levels, reducing neuroprotection in the brain.

Psychiatr Danub. 2012 Sep;24 Suppl 1:S95-9.The differences between typical and atypical antipsychotics: the effects on neurogenesis.Nandra KS, Agius M.Clare College Cambridge, Cambridge, UK.

Growth Factor and Antipsychotics

Long Term Antipsychotic Treatment and Brain Volumes: A longitudinal Study of First-Episode Schizophrenia

An average of 7.2 years of continuous typicalantipsychotic therapy was associated with generalized and specific reductions in brain tissue.

Archives of General Psychiatry. 2011;68(2):128-137.doi: 10.1001/archgenpsychiatry.2010.199

TD as an Indicator of Tissue Loss

1 Year Incidence of TD with Atypical vs. Typical Antipsychotics

Kane JM in Bloom FE, Kupfer DJ, Psychopharmacology: The fourth generation of progress. Philadelphia Raven 1996National Alliance on Mental illness. Tardive dyskinesia Available at www.nami.org/ContentGroups/Helpline1/Tardive_Dyskinesia.html

Schizophrenia and Brain Tissue Loss MRI image of an averaged profile of brain tissue loss from a group of

patients with early- onset schizophrenia (5 years interval)

Thompson, P.M. et al: Mapping Adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA 98, 11650-11655

Mechanism of Brain Tissue Loss

Schizophrenia is a disease of progressive reductions in grey matter, and the more lost, the worse the outcome.

Schizophrenia is not a disease that kills massive amounts of cells, the way Alzheimer’s disease does.

In schizophrenia primarily there is a loss of cell processes, because of low levels of neurotrophins e.g. NT-3, NGF, GDNF, BDNF

Psychiatr Danub. 2012 Sep;24 Suppl 1:S95-9.The differences between typical and atypicalantipsychotics: the effects on neurogenesis. Nandra KS, Agius M. Clare College Cambridge, Cambridge, UK.

The Brain is Made Mostly of Dendrites

Dendrites - the Canopy of Our Brain Forest

Apoptosis Comparison: Autism, Schizophrenia, Alzheimer’s

Alzheimer’s - massive cell apoptosisSchizophrenia - apoptosis of cell processes (dendrites)

Cortical Pyramidal Neurons

Apoptotic mechanisms and the synaptic pathology of schizophrenia; Leisa A. Glantza, John H. Gilmorea, Jeffrey A. Liebermanb, L. Fredrik Jarskoga, , Department of Psychiatry, University of North Carolina—Chapel Hill, CB# 7160, Chapel Hill, NC 27599-7160, U.S.A.b Department of Psychiatry, Columbia University, New York, NY 10032, U.S.A.http://dx.doi.org/10.1016/j.schres.2005.08.014,

Metabolomic Biomarkers in Schizophrenia

The following set of metabolic biomarkers have identical sensitivity and specificity as the MSE

Glycerate Eicosenoic acid Beta-hydroxybutirate Pyruvate Cysteine Urine beta hydroxybutirate

Potential Metabolite Markers of Schizophrenia; J. Yang et al.; Molecular Psychiatry(213) 18, 67-78; doi:10.1038/mp.131

Patient-Specific Neurons Obtained by Cellular Reprogramming

Cultured Patient Specific Neurons Exposed to Antipsychotics or Neuroprotective Agents Personalized Medicine Ability to identify medications that work

best for a specific individual prior to the initiation of therapy.

Modeling Schizophrenia Using Human Induced Pluripotent Stem Cells;Kristen J. Bernnand et al.; Nature

473, 221-225 (12 May 2011) doi:10.1038/nature09915

Patient Specific Cultured Neurons Exposed to Loxapine

Cultured neurons from patients with schizophrenia present with decreased neuronal connectivity.Adding Loxapine resulted in improvement in neuronal connectivity

Modeling Schizophrenia Using Human Induced Pluripotent Stem Cells;Kristen J. Bernnand et al.; Nature473, 221-225 (12 May 2011) doi:10.1038/nature09915

Analysis of Dendritic Spine Density and Morphology in Cultured Neurons

Software for high-resolution imaging of dendritic spines in cultured live neurons.

Future Treatment AlgorithmDx by MSE verified by

Schizophrenia

metabolomic panel

Determine the affected

domain of schizophrenia

Choosing best therapy

(cultured patient specific

neurons)

Assessment of Tx efficacy

(dendritic spine density measurement

)

Staging of the illness

(fMRI +connectomic

s)

The best way to become boring is to say everything.

Voltaire