3. Serotonin
5HT2A/dopamine D2
RISPERIDONE antagonist
ILOPERIDONE-FDA
approved for acute
treatment of
schizophrenia in
ILOPERIDONE adults.
4. 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.
5. 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
6. Serotonin
ASENAPINE
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
7. 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
8. 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
9. 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.
10. 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
11. EPS and akathisia, but seems to be reduced if
taken at night.
Will require confirmation from real world
clinical experience.
12.
13. 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.
14. 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.
15. 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.
16.
17. The old paradigm:
Antipsychotic drugs are efficacious because
they increase, decrease or alter
the neurotransmitters at synapses throughout
the brain, thus correcting
neurotransmission.
18. 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.
19. The new 21st century antipsychotic drugs will
aim 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.
20. 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
21.
22. 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.
23. Events that shaped the development of
antipsychotics 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.
24. 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.
25. Gene mining took the proportion of a “gold rush.”
A gene for everything was envisioned.
27. GENES DID NOT TELL US THE STORY WE WANTED TO HEAR
28. Human Genome did not evolve to validate DSM IV
criteria of mental illness.
This raises serious questions about psychiatric
taxonomy.
29. 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.
30. Genes are nothing more than risk
factors for psychopathology.
For instance schizophrenia risk genes code for:
-Neuronal migration,
-Neuronal differentiation,
-Synaptogenesis,
-Synaptic plasticity and
-Cytoskeleton
Genes point to brain wiring.
31. 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.
32. Forest Gump would probably say: “The brain
is like a plate of spaghetti”.
33.
34. 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.
35.
36. 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.
37. The effectiveness of atypical antipsychotics
questioned
38. 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.
39. 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.
43. 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 cognitive
symptoms
44. 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.
45. 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.
