'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.
An overview of atypical anti depressantsBrajesh Lahri
This powerpoint presentation deals with the pharmacology and psychiatric uses of atypical anti-depressants. TCAs and SSRIs are considered as typical anti-depressants, while other classes include SNRI, RIMAs and atypical antidepressants. In this presentation, i have briefly given an overview of atypical anti-depressants as well as of SNRIs and RIMAs.
An overview of atypical anti depressantsBrajesh Lahri
This powerpoint presentation deals with the pharmacology and psychiatric uses of atypical anti-depressants. TCAs and SSRIs are considered as typical anti-depressants, while other classes include SNRI, RIMAs and atypical antidepressants. In this presentation, i have briefly given an overview of atypical anti-depressants as well as of SNRIs and RIMAs.
The video for this presentation is available on our Youtube channel:
https://youtube.com/allceuseducation A continuing education course for this presentation can be found at https://www.allceus.com/member/cart/index/index?c=
Psychopharmacology: Antidepressants, Antipsychotics and Mood Stabilizers
Dr. Dawn-Elise Snipes PhD, LPC-MHSP, LMHC, NCC, CCDC
Executive Director, AllCEUs.com
Objectives
For each of the following, antidepressants, antipsychotics and mood stabilizers
Examine their method of action
Explore the types of disorders they are used to treat
Review the most common medications in those classes
Identify where to get more information for patients
Discuss the benefits and drawbacks to off-label prescribing
This is a project for a high school AP Psychology course. This is a fictionalized account of having a psychological ailment. For questions about this blog project or its content please email the teacher Chris Jocham: jocham@fultonschools.org
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...Dr. Rafael Higashi
Aula apresentada por Dr. Rafael Higashi, médico neurologista sobre quando retirar droga antiepilética. A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement
Molecular Substrates of Drug Abuse in a Schizophrenic PopulationAlan Lesselyong
This presentation is a Work In Progress (WIP) covering experiments examining the molecular correlates of drug abuse in human brains diagnosed with schizophrenia
Psychotherapy the biological dimensionismail sadek
is it real word can affect your brain?
many people say not and don't believe that the psychotherapy change not only our behavior but also it can change the brain structure
No association between prepulse inhibition of the startle reflex and neuropsyc...Benjamin Cortes
Abstract: Sensorimotor gating deficits are relevant in schizophrenia and can be measured using prepulse inhibition (PPI) of the startle reflex. It is conceivable that such deficits may hinder the cognitive functions in schizophrenia patients. In this study, using PPI and a neuropsychological battery, we studied this possibility in a group of 23 acute, neuroleptic-free schizophrenia patients and 16 controls. A non-significant decrease in PPI was found in the patients as compared to the controls, as well as significant differences in the performance of Trail A and B in Wisconsin
Card Sorting and Digit/Symbol Tests. No statistically significant correlations between PPI and neuropsychological performance were found after the correction for multiple comparisons in any group. Our results suggest that PPI deficits in schizophrenia patients may not contribute to the cognitive deficits typical of that illness, at least in patients with a non-significant PPI decrease.
Novel psychoactive substances include synthetic cannabinoids, cathinone derivatives, psychedelic phenethylamines, novel stimulants, synthetic opioids, tryptamine derivatives, phencyclidine-like dissociatives, piperazines, GABA-A/B receptor agonists, a range of prescribed medications, psychoactive plants/herbs, and a large series of performance and image enhancing drugs. Users are typically attracted by these substances due to their intense psychoactive effects and likely lack of detection in routine drug screenings. This paper aims at providing psychiatrists with updated knowledge of the clinical pharmacology and psychopathological consequences of the use of these substances. Indeed, these drugs act on a range of neurotransmitter pathways/receptors whose imbalance has been associated with psychopathological conditions, including dopamine, cannabinoid CB1, GABA-A/B, 5-HT2A, glutamate, and k opioid receptors. An overall approach in terms of clinical management is briefly discussed.
Similar to Hans Jürgen-Current situation and future perspetives of antipsychotics in schizoprenia (20)
Jordi Torren - Coordinador del proyecto ESVAC. Agencia Europea de Medicamento...Fundación Ramón Areces
El martes 5 de junio del 2018 organizamos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre el consumo de antibióticos y transmisión de resistencia entre humanos y animales.
Dominique L. Monnet Director del programa ARHAI (Antimicrobial Resistance an...Fundación Ramón Areces
El martes 5 de junio del 2018 organizamos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre el consumo de antibióticos y transmisión de resistencia entre humanos y animales.
El jueves 24 de mayo del 2018 organizamos una Conferencia con Antonio Cabrales en la Fundación Ramón Areces. Una conferencia en la cual el tema fue: Estilo negociador y confianza, ¿hay diferencias entre hombres y mujeres?
Teresa Puig - Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Espa...Fundación Ramón Areces
El lunes y martes 21 y 22 de mayo del 2018 realizamos un Simposio Internacional en la Fundación Ramón Areces, tratando el tema de la superconductividad y presión: una relación fructífera en el camino hacia la superconductividad a temperatura ambiente.
Elena Bascones - Instituto de Ciencia de Materiales de Madrid (ICMM-CSIC), Es...Fundación Ramón Areces
El lunes y martes 21 y 22 de mayo del 2018 realizamos un Simposio Internacional en la Fundación Ramón Areces, tratando el tema de la superconductividad y presión: una relación fructífera en el camino hacia la superconductividad a temperatura ambiente.
El jueves 17 de mayo del 2018 se organizó una Mesa Redonda en la Fundación Ramón Areces, en la cual se habló sobre las subidas de tipos en la era Trump y la nueva globalización.
El jueves 17 de mayo del 2018 se organizó una Mesa Redonda en la Fundación Ramón Areces, en la cual se habló sobre las subidas de tipos en la era Trump y la nueva globalización.
El miércoles 16 de mayo del 2018 celebramos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre las nuevas fronteras de investigación sobre la distribución comercial y el comportamiento del consumidor.
El miércoles 16 de mayo del 2018 celebramos una Jornada en la Fundación Ramón Areces, en la cual se habló sobre las nuevas fronteras de investigación sobre la distribución comercial y el comportamiento del consumidor.
Juan Carlos López-Gutiérrez - Unidad de Anomalías Vasculares, Hospital Unive...Fundación Ramón Areces
El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
Víctor Martínez-Glez. - Instituto de Genética Médica y Molecular (INGEMM). I...Fundación Ramón Areces
El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
Rudolf Happle - Dermatología, University of Freiburg Medical Center, Freiburg...Fundación Ramón Areces
El jueves y viernes 10 y 11 de mayo del 2018 realizamos en la Fundación Ramón Areces un Simposio Internacional, en el cual se trató el tema del mosaicismo somático en malformaciones vasculares.
Rafael Doménech - Responsable de Análisis Macroeconómico, BBVA Research. Fundación Ramón Areces
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
Nicholas Barr - Profesor de Economía Pública, London School of Economics. Fundación Ramón Areces
El martes 8 de mayo de 2018 realizamos una conferencia en la Fundación Ramón Areces, en la cual se habló sobre el futuro de las pensiones: una visión global.
El viernes 27 de abril del 2018 se celebró en la Fundación Ramón Areces una Jornada sobre física , en la cual se trataron diversos temas como: Los materiales mecanocalóricos, magnetísmo, biofísica, la energía oscura y instrumentación astronómica.
El viernes 20 de abril organizamos una Jornada sobre la ciencia en el corazón de Europa, en colaboración con Científicos Españoles en Bélgica (CEBE) y realizada en la Fundación Ramón Areces.
Marta Olivares - Investigadora Postdoctoral en Université catholique de Louva...Fundación Ramón Areces
El viernes 20 de abril organizamos una Jornada sobre la ciencia en el corazón de Europa, en colaboración con Científicos Españoles en Bélgica (CEBE) y realizada en la Fundación Ramón Areces.
El viernes 20 de abril organizamos una Jornada sobre la ciencia en el corazón de Europa, en colaboración con Científicos Españoles en Bélgica (CEBE) y realizada en la Fundación Ramón Areces.
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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