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

4. D2 Blockade

5. D2 and 5HT2A Blockade

6. FDA Approved Antipsychotics This
Decade
 Aripiprasol(2002)
 Fazaclo (Sept, 14, 2005)
 Paliperidone (December 19, 2006)
 Illoperidone (May 7, 2009)
 Asenapine (August 15, 2009)
 Lurasidone (October 29, 2010)

7. 21st Century Psychiatry

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

9. From Freud to Prozac

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

12. Computational Paradigm
Putting Brains Back in Psychiatry

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

15. Advances in Functional MRI
 fMRIrevealed:
the brain to be a highly connected organ

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

17. Automated Tape-Collecting
Ultramicrotome (ATUM)

18. Cellular Connectomics

19. Connectomics in Schizophrenia
Bullmore&Sporns, Nat Rev Neuroscii 2009

20. Schizophrenia : fronto-temporal dysconnectivity
Graph Analysiss
schizophrenia
patients
healthy
subjects
Nodes= small ,
large or average
clustering

21. Psychosis

22. 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

23. 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)

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

29. FDA Indications

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

40. Both Psychosis and Some
Antipsychotics Cause Brain Tissue Loss

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.

43. Growth Factor and Antipsychotics

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.

48. The Brain is Made Mostly of
Dendrites

49. Dendrites - the Canopy of Our
Brain Forest

50. Apoptosis Comparison: Autism,
Schizophrenia, Alzheimer’s

51. Alzheimer’s - massive cell apoptosis
Schizophrenia - apoptosis of cell
processes (dendrites)

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

54. Patient-Specific Neurons Obtained
by Cellular Reprogramming

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