This document discusses psychosis, antipsychotics, and the brain. It begins with definitions of psychosis and descriptions of biological markers and FDA-approved antipsychotics of the past decade. It then discusses computational models of psychosis and the relationship between psychosis, antipsychotics, and brain tissue loss. The document also discusses patient-specific cultured neurons and summarizes key points about conventional versus atypical antipsychotics. The rest of the document details various antipsychotics approved in the past decade, events shaping antipsychotic development, advances in neuroimaging and connectomics in schizophrenia research. It discusses causes and substances related to psychosis and default mode networks in the brain. The document concludes by discussing brain changes associated with antip
1. Psychosis and
Antipsychotics
ADONIS 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
2. What Makes an Antipsychotic Conventional?
D2 Antagonist Actions
D2
3. What Makes an Antipsychotic Atypical?
-D2 antagonist action
-5HT2A antagonist action
5HT2A
D2
8. Events that Shaped the Development of
Antipsychotics 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
10. The Brain as a Black Box
Upbringing determines the output
19th and early 20th century paradigm
11. Biochemical Paradigm
From blaming the mother to blaming neurotransmitters
Second half of the 20th century
1954 discovery of Chlorpromazine
Psychopharmacology
The biochemical trinity:
-dopamine
-serotonin
- norepinephrine
13. 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
14. Large Brain Networks
The salience network initiates dynamic switching between the central-
executive and default-mode networks, and mediates between attention
to endogenous and exogenous events.
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
16. 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
24. 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.
25. 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
26. Brain’s “Default Mode” Awry in
Schizophrenia
American Journal of Psychiatry 164: 450-457 (March 2007)
27. Newest Antipsychotics Advantages
Iloperidone (Fanapt) Asenapine Lurasidone
Efficacy comparable to other Mild metabolic risk; no prolactin Lack of affinity at H1 and
atypicals elevation M1receptors allows treatment to
begin at therapeutically effective
dose; rapid onset of action
Not approved for mania, but No dose titration needed 40-80 mg/day effective for acute
potentially effective. exacerbation of schizophrenia
Has very low (placebo-level) EPS Long half-life; once-daily dose is Appears to have a benign
and little or no akathisia theoretically possible metabolic profile without
affecting QTc prolongation; low
EPS
Potent alpha 1 blocking Sublingual tablet good for Once-daily administration is
properties suggest potential utility reliable, compliant patient possible
in PTSD
Binding properties suggest Not approved for depression, but
theoretical efficacy in depression binding profile suggests potential
use in treatment resistant cases
28. Newest Antipsychotics Disadvantages
Iloperidone Asenapine Lurasidone
Dose-dependent QTc Not absorbed once swallowed; EPS and akathisia, but seems to
prolongation must be administered be reduced if taken at night
sublingually
Slow titration Common side effect: oral Will require confirmation from
hypoesthesia real world clinical experience
Use caution with patients Patients may not eat or drink
sensitive to orthostasis (young, for 10 minutes after
elderly, CV problems) administration to increase
bioavailability
In presence of 2D6 inhibitors Somnolence/sedation/EPS
(paroxetine, fluvoxamine, dulox
etine) reduce dose by half
Weight gain/metabolic profile Inhibits 2D6 and is a substrate
comparable to Risperidone for 1A2
30. Iloperidone Dosing
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1 mg 2 mg 4 mg 6 mg 8 mg 10 mg 12 mg
BID BID BID BID BID BID BID
31. 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
32. Asenapine Dosing
Sublingual 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
33. Asenapine Tolerability
Limited 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
34. Lurasidone Dosing
Recommended starting dose 40 mg/day
Maximum recommendined dose was originally
80 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 with
moderate to severe renal or hepatic impairment.
35. Lurasidone Tolerability
Benign 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
36. Cariprazine
D2 partial agonist
-more of an antagonist than Aripiprazole
In 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
37. 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 4th ed 2011
38. 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
39. 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
41. 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.
42. 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.
44. Long Term Antipsychotic Treatment and Brain
Volumes: A longitudinal Study of First-Episode
Schizophrenia
An average of 7.2 years of continuous typical
antipsychotic 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
45. 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 1996
National Alliance on Mental illness. Tardive dyskinesia Available at
www.nami.org/ContentGroups/Helpline1/Tardive_Dyskinesia.html
46. 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
47. 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 atypical
antipsychotics: the effects on neurogenesis. Nandra KS, Agius M. Clare College Cambridge,
Cambridge, UK.
52. 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,
53. 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
55. 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
56. 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.; Nature
473, 221-225 (12 May 2011) doi:10.1038/nature09915
57. Analysis of Dendritic Spine Density and
Morphology in Cultured Neurons
Software for high-resolution imaging of dendritic
spines in cultured live neurons.
58. Future Treatment Algorithm
Dx by MSE
Determine the
verified by
affected
Schizophrenia
domain of
metabolomic
schizophrenia
panel
Staging of the
illness (fMRI
+connectomics)
Choosing best Assessment of
therapy Tx efficacy
(cultured (dendritic spine
patient specific density
neurons) measurement)
59. The
best way to become boring is to say
everything.
Voltaire