'Psiquiatría: situación actual y perspectivas de futuro'. Este es el título del simposio internacional que organizamos el 16 de junio de 2016 en la Fundación Ramón Areces con las fundaciones Juan José López-Ibor y Lilly en homenaje al doctor Juan José López-Ibor, fallecido en enero de 2015. Durante esta jornada, expertos internacionales abordaráon la profunda crisis que atraviesa la psiquiatría como disciplina científica y especialidad médica. Además, a las 19.00 horas, se presentará el libro con el mismo título del simposio, también en recuerdo del doctor López-Ibor.
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Hans Jürgen-Current situation and future perspetives of antipsychotics in schizoprenia
1. Prof. Dr. med. Dr. h.c. mult. H.-J.
Möller
Psychiatric Department
Ludwig-Maximilian-University
Munich
Current situation and future
perspectives of
antipsychotics in
schizophrenia
http://psychiatrie.klinikum.uni-muenchen.de
4. Anripsychotics: Approved in the last
decade
Asenapine
Iloperidone
Lurasidone
Paliperidone
Olanzapine pamoate (2-4 w)
Abilify maintena (4w)
Paliperidone palmitate (4w or 3m)
5. Leucht et al. 2009: Lancet 3;373(9657):31-41
Second-generation versus first-generation
antipsychotic drugs - efficacy in various
domains
6. Efficacy of 15 antipsychotics vs. placebo
(PANSS/BPRS Summenscore)
reduction of total score compared to placebo
Clozapine -0.88 (-1.03 to -0.73)
Amisulpride -0.66 (-0.78 to -0.53)
Olanzapine -0.59 (-0.65 to -0.53)
Risperidone -0.56 (-0.63 to -0.50)
Paliperidone -0.50 (-0.60 to -0.39)
Zotepine -0.49 (-0.66 to -0.31)
Haloperidol -0.45 (-0.51 to -0.39)
Quetiapine -0.44 (-0.52 to -0.35)
Aripiprazole -0.43 (-0.52 to -0.34)
Sertindole -0.39 (-0.52 to -0.26)
Ziprasidone -0.39 (-0.49 to -0.30)
Chlorpromazine -0.38 (-0.54 to -0.23)
Asenapine -0.38 (-0.51 to -0.25
Lurasidone -0.33 (-0.45 to -0.21)
Iloperidone -0.33 (-0.43 to -0.22)
SMD (95% confidence intervall)
-1 -0.5
in favour of medication
0
Leucht et al. Lancet. 2013 Sep 14;382(9896):951-62
7. Evidence based medicine
Sackett et al. 1996, BMJ 312:71-72
Evidence based medicine is the conscientious, explicit
and judicious use of current best evidence in making
decisions about the care of individual patients
The practice of evidence based medicine
means integrating individual clinical expertise
with the best available external clinical
evidence from systematic research
9. Antipsychotic drug effects on MRI brain
morphology in first-episode psychosis
Mean changes in whole brain grey
matter volumes by treatment
group (from baseline to weeks 12,
24, 52, and 104) and healthy
control group (from baseline to
weeks 12 and 52)
Hal = haloperidol
Olz = olanzapine
Con = controls
Limit lines = standard error
Lieberman et al. 2005, Arch Gen Psychiatr 62: 361-
10. Krebs et al. 2006, Expert Opinion 7:837-848
Lieberman et al. 2012, Pharmacological Reviews
Neuroprotective properties of second-
generation antipsychotics
+: Neuroprotective effect; ± No effect; BDNF: Brain-derived neurotrophic factor; MPP: 1-Methyl-4-
phenylpyridinium; NGF: Nerve growth factor; SOD: Superoxide dismutase.
References Method Mechanism
Neuropro-
tection
Olanzapine
Angelucci et al. 2005, Animal model (rats) NGF increase (hippocampus)
+ Parikh et al. 2004 Rat hippocampus
Bai et al. 2003, Animal model (rats) BDNF increase (hippocampus)
+
Wakade et al. 2003, Kodama Animal model (rats) Increased neurogenesis
+ et al. 2004, Wang et al. 2004
Quing et al. 2003 PC12 cell cultures (MPP+) Prevention of cell death
+
Bai et al. 2002 PC12 cell cultures (serum withdrawal) Prevention of cell death
+
Wei et al. 2003 PC12 cell cultures (hydrogen peroxide) Prevention of cell death
+
Bai et al. 2002, Li et al. 1999 PC12 cell cultures SOD1 increased
+
Parikh et al. 2003 Rat brain homogenates No change of SOD
±
+
11. Patient after 12 weeks‘ quetiapine treatment:
significantly improved representation of working
memory
Talairach:
X = -39
Y = 41
Z = 24
T= 3.1 T= 3.1
Mid-frontal
gyrus
Brodmann: 9
Before treatment After treatment
Meisenzahl EM et al. 2006, Eur
Arch Psychiatry Clin Neurosci
12. Ettinger et al. 2011: Psychopharmacology; 216(1):17-2
Abstract
We used functional magnetic resonance imaging (fMRI) and studied the blood
oxygen level dependent (BOLD) response of 45 stable schizophrenia outpatients
and 19 matched healthy controls during a parametric n-back working memory task.
Imaging revealed that patients produced stronger BOLD signals in occipital and
lateral prefrontal cortex than controls and that this difference increased with
increasing working memory load in the additionally recruited prefrontal areas.
Second-generation antipsychotics were independently associated with a left
prefrontal BOLD increase in response to working memory load, whereas first-
generation antipsychotics were associated with BOLD decrease with increasing load
in this area.
Together, these findings suggest that in schizophrenia patients normal working
memory task performance may be achieved through enhanced neural activity,
especially in well performing patients and in those treated with second-generation
antipsychotics.
14. Ho et al. 2011, Arch Gen Psychiatr 68(2): 128-37
Key Points
• During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices
in 1991 through 2009.
• Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid
volumes
• Greater intensity of antipsychotic treatment was associated with indicators of generalized and
specific brain tissue reduction after controlling for effects of the other 3 predictors.
• More antipsychotic treatment was associated with smaller gray matter volumes. Progressive
decrement in white matter volume was most evident among patients who received more
antipsychotic treatment.
• Illness severity had relatively modest correlations with tissue volume reduction, and
alcohol/illicit drug misuse had no significant associations when effects of the other variables
were adjusted
Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle
but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-
benefit review of dosage and duration of treatment as well as their off-label use
16. Möller HJ, 2012, Curr Pharm Biotechnol.
Currently drugs in development are based on the classical
transmitter related approaches, following especially the
model of clozapine and several other multi-receptor compounds.
More and more, the glutamergic and other
transmitter systems are of interest in this context as well.
Totally new directions, e.g. based on genetic findings or
focussing more on brain plasticity are headed for.
The question is, whether beside the classical concept of
antipsychotics, which covers all symptomatic
domains of schizophrenia, compounds demonstrating
efficacy only in one syndrome such as e.g. negative
symptoms will have a chance in the future development.
17. Lopez-Munoz F and Alamo C 2011: Clinical Neuropharmacology 34 (3); 111-26
Antipsychotic drugs in development (I)
18. Lopez-Munoz F and Alamo C 2011: Clinical Neuropharmacology 34 (3); 111-26
Antipsychotic drugs in development (II)
19. Lopez-Munoz F and Alamo C 2011: Clinical Neuropharmacology 34 (3); 111-26
Key points
• Among the most promising mechanisms are those based on the
glutamatergic hypothesis of schizophrenia (agonists at the glycine-
binding modulatory site of the N-methyl-D-aspartate receptor, glycine
transporter inhibitors, modulators of the AMPA [>-amino-3-hydroxy-
5-methyl-4- isoxazolepropionic acid] receptor and selective agonists
of the metabotropic receptor Glu2).
• Other less classic pathways are also under study and have led to
some agents that are found in very early stages of development such
as those acting on acetylcholine receptors, sigma receptors,
cholecystokinin antagonists, neurotensin agonists, neurokinin
receptor antagonists, GABAergic (+-aminobutyric acid [GABA])
enhancers, and cannabinoid( gamma-aminobutiric) receptor
modulators.
20. •Phencyclidine (PCP) and other NMDA receptor antagonists
induce a psychosis with both positive and negative symptoms as
well as formal thought disorder,
• In monkeys and rats, selective NMDA receptor blockage generates
severe behavioral and cognitive abnormalities, including impaired
working memory
• A mouse model expressing only 5% of normal levels of one of the
essential NMDA receptor (NR1) subunits displays behavioral
abnormalities, similar to those observed in other animal models of
schizophrenia
• Postmortem studies have demonstrated impaired expression of
several NMDA receptor subtypes in the prefrontal cortex of
schizophrenic patients (but more recently also in bipolar disorder
and major depression)
Glutamate hypothesis of
schizophrenia
Feyissa et al 2009: Prog Neuropsychopharmacol Biol Psychiatry;70-5
Beneyto M and Meador-Woodruff J 2008: Neuropsychopharmacology 33,
2175–2186
Kantrowitz and Javitt, 2010, Brain Research
21. Lopez-Munoz F and Alamo C 2011: Clinical Neuropharmacology 34 (3); 111-26
Glycine/glutamat
e transporters
(light square)
and AMPA
receptor/mGlu
receptors (dark
square) as
therapeutic
targets of
antipsychotic
drugs
22. Umbricht D et al. 2010: Neuropsychopharmacol; 35(S1): s320
23. Patil et al. 2007:
Nature Medicine 13(9): 1102-
Ly 404039, a selective agonist for the
mGlu2/3 receptor: first clinical study
24. Cholinergic agonists as treatment for
schizophrenia
Liebermann et al, 2008
e.g.
• DMXB-A: A cholinergic nicotinic partial agonist selective
for the Alpha-7 receptor (Friedman et al 2008)
• Xanomeline: a muscarinic cholinergic agonist with
relative selectivity for M1 and M4 receptors (Shekhar et
al 2008)
25. Clinical studies of selective COX-2
inhibitors in schizophrenia
Authors Diagnosis Course and
duration
Duration
of trial
N Study design Concomitant
drug
COX-2
inhibitor
Outcome
Zhang et al,
2006
schizophrenia First
manifestation
12 weeks 40 double-blind,
randomized
placebo-controlled
add-on
Risperidone
(flexible
dose)
Celecoxib
400 mg/day
significant
advantage of
the COX-2
inhibitor
Müller et al,
2002
schizophrenia Not specified
mean 5,9 y
5 weeks 50 double-blind,
randomized
placebo-controlled
add-on
Risperidone
(flexible
dose)
Celecoxib
400 mg/day
significant
advantage of
the COX-2
inhibitor
Rappard and
Müller, 2004
schizophrenia ≤ 10 years 11 weeks 270 double-blind,
randomized
placebo-controlled
add-on
Risperidone
(flexible
dose)
Celecoxib
400 mg/day
non advantage
of the COX-2
inhibitor
Rapaport
et al, 2005
schizophrenia Continuously ill
mean 20 y
8 weeks 38 double-blind,
randomized
placebo-controlled
add-on
Risperidone
or Olanzapine
(constant
dose)
Celecoxib
400 mg/day
non advantage
on the COX-2
inhibitor
Akhondzadeh
et al, 2007
schizophrenia Chronic type
(active phase)
8 weeks 60 double-blind,
randomized
placebo-controlled
add-on
Risperidone
(fixed dose)
Celecoxib
400 mg/day
significant
advantage of
the COX-2
inhibitor
26. Singh et al; The British Journal of Psychiatry (2010); 197, 174–179. doi: 10.1192/bjp.bp.109.067710
28. • Insufficient number of studies with sound methodology and
often inconsistent results
• FGAs and especially some SGAs demonstrated efficacy in
negative symptoms secondary to positive symptoms
• Especially treatment studies on primary or persistent negatvie
symtpoms rare
• Limited efficacy on predominant/persistent proven for
• - some SGAs
• - some antidepressants, especially SSRIs and mirtazapine, in
comedication with antipsychotics
• - some glutamatergic compounds like glycine , d-serine,
• ( bitopertine)
29. Thus, research on the exact interplay between
glutamergic neurotransmission and neuronal
proliferation deserves more attention. This dual in
vivo and in vitro strategy described here may prove
as a suitable model for addressing complex
neuropsychiatric diseases especially when taking
advantage of the potential of multiplex
technologies not only in diagnostics but also in
basic research. Genius J., et al, 2012, Elsevier
30. Wilson C. Terry A.V., 2010, Clinical Schizophrenia & Rel. Psychoses.
The purpose of this review is to provide a general overview of
the various neurodevelopmental models of schizophrenia that
have been introduced to date, and to summarize their
behavioral and neurochemical phenotypes that my be useful
from a drug discovery and development standpoint. While it
may be that, in the final analysis, no single animal model will
satisfy all the requirements necessary for drug discovery
purposes, several of the models may be useful for modeling
various phenomenological and pathophysiological
components of schizophrenia that could be targeted
independently with separate molecules or multi-target drugs.
32. • Findings from genetic research emphasize the potential for schizophrenia
risk genes to help develop focused treatments, discover new drug targets
and provide markers of clinical subtypes.
• Advances in genetic technologies also provide novel modes of drug
discovery in
schizophrenia such as transcriptomics, epigenetics and transgenic
animal models.
• In this review, we discuss proven and proposed ways risk genes can be
used to enhance the development and discovery of treatments for
schizophrenia and highlight key studies in these approaches.
O‘Connel G. et al, 2011, Biochem Pharmacol.
38. Possible RoadMap for Stimulating Drug Discovery in Schizophrenia
1. Select a validated neurobiologocal pathway
2. Identify target mechanism
3. Identify clinical compounds by screening
4. Validate hits in vitro and in vivo
Option A:
Initiate Clinical Trial
for secondary application
based on preclinically
validated mechanism
Option B:
Convince industrial partners
to initiate a new drug discovery program
based on preclinically
validated mechanism
39. NRG1: One of the 107 risk genes
for schizophrenia
Ripke S, et al. 2013: Nature Genetics
The Neuregulins control the assembly of
neuronal circuitry, myelination,
neurotransmission and synaptic plasticity
(Mei and Nave, Neuron, 2014)
40. Erbb4+/-
Parv-Cre x Erbb4fl/fl
Nrg1+/-
Agarwal et al, Cell Reports, 2014
Mei, Marin, Weinberger, Law,
Schwab Labs
Emx-Cre x Nrg1fl/fl
NRG1 Val->Leu in TM
Seltene Variante in SZ
Walss-Bass et al, 2006
Chen et al., 2012
NRG1
ERBB4
PI3K
Association with Schizophrenia
Thy1-Nrg1III
Agarwal et al, Cell Reports 2014
Weickert et al, 2012
Brennand et al., 2012
NRG1III mRNA erhöht
pERBB4 erhöht
Hahn et al, 2006
tetO-Nrg1I
Yin et al, Neuron 2013
Mei, Schwab Labs
CamKII-Cre x Nrg1fl/fl
Nrg1IIIt
g
Markus Schwab
41. Hinrichs, Wehr et al., unpubl.
Best ‚Hit‘ = Spironolactone
Mineralcorticoid-Receptor + ERBB4 Inhibitor
ERBB4
pY984 ERBB4
Tub
10ng/ml EGFld
Canrenone Spironolactone
Nrg1-EGFld
p-ERBB4
Tubulin
Can Spiro
HEK293
O
O
O
Cytotox
ERBB4/PI3K
Aktivität(%)
PC12
O
S
O
O
O
Cytotox
ERBB4/PI3K
IC50 = 0.7 µM
Aktivität(%)
42. Spiro-Trial funded by Stanley foundation
LMU/TU München – Falkai/Hasan
Option A:
Initiate Clinical Trial for secondary application
based on preclinically validated mechanism
57. Antipsychotics: Potential mechanisms of antidepressive
efficacy
Yatham et al. 2005; Brugue and Vieta 2007; Goldstein et al. 2007
Antidepressant
Effect
A2
Antagonism
5-HT2A
antagonism
Modulation
of dopamine
levels
5-HT2A
down-regulation
NET
antagonism
60. Summary: DrugTreatmentPerspectives
Second-generation antipsychotics with their specific pharmacology induce fewer EPS
symptoms, have a broader spectrum of efficacy and could thus improve outcome
Early recognition and treatment, as well as better relapse prevention, could be possibilities
to improve the outcome of schizophrenic patients
New antipsychotics, amongst other focussing on the glutamatergic system are in
development
Co-treatment of the immunological alterations (e.g. cox-2 inhibitors) can improve
treatment outcome
Can we adress the neurodevelopmental and neuroprogressive processes directly (e.g.
neurites outgrowth promoters)?
Genetic findings will hopefully lead to the detection of other innovative therapeutic
mechanisms
In future, pharmacogenetics may play a major role in treatment decision-making: “Genetic
fingerprint”
61. Thank you for
your attention!
Munich – Psychiatric University Department
http://psychiatrie.klinikum.uni-muenchen.de