psychotic-like symptoms in neurological patients : beyond the dopaminergic hypothesis riccardo torta...

Psychotic-like symptoms Psychotic-like symptoms in neurological patients : in neurological patients :

beyond the dopaminergic hypothesisbeyond the dopaminergic hypothesis

Riccardo TortaRiccardo TortaSCDU Psicologia Clinica e OncologicaSCDU Psicologia Clinica e Oncologica

DipartimentDipartimenti i di Neuroscienzedi Neuroscienze ed Oncologia ed Oncologia

Università di TorinoUniversità di Torino

Summer School of NeuroscienceSummer School of NeuroscienceJuly 12July 12thth, 2007, 2007

PsychosesPsychoses

Behavioural DisordersBehavioural Disorders

PsychosesPsychoses

Behavioural DisordersBehavioural Disorders

DementiaDementiaDementiaDementia

ParkinsonParkinsonParkinsonParkinsonEpilepsyEpilepsyEpilepsyEpilepsy

nosographic problemsnosographic problems

therapeutic problemstherapeutic problems

BPSDBPSD Euphoria - PsycosesEuphoria - Psycoses

SLPESLPE

Drug inducedDrug inducedDrug inducedDrug induced

Drug inducedDrug induced

HallucinosisHallucinosis

MSMSMSMS

Brain metabolism in dementia: Brain metabolism in dementia: relationship to emotional symptomatologyrelationship to emotional symptomatology

Sultzer DL. et al 1996Galynker et al., 2000

Agitation/disinhibition

Psychosis

Delusionalthoughts

(hypometabolism)

Temporal

Subjectivemood symptoms

HighLow

Anteriorcingulate

Fro

nta

l

Pre

fron

tal

Fron

tal

Par

ieta

lpole

Anxiety/depression

Apathy

BPSDBPSDBPSDBPSD

NeurolepticsNeurolepticsNeurolepticsNeuroleptics

AED as AED as Mood Mood stabilizersstabilizers

AED as AED as Mood Mood stabilizersstabilizers

Beta-blockersBeta-blockersBeta-blockersBeta-blockers Serotoninergic Serotoninergic drugsdrugs

Serotoninergic Serotoninergic drugsdrugs

BenzodiazepinesBenzodiazepinesBenzodiazepinesBenzodiazepines Atypical Atypical antipsychoticsantipsychotics

Atypical Atypical antipsychoticsantipsychotics

R.Torta, E. Badino, A. Scalabrino THERAPEUTIC STRATEGIES FOR BEHAVIORAL

AND PSYCHOLOGICAL SYMPTOMS IN DEMENTED PATIENTSArch Gerontol Geriatr. 2004

CLINICAL CLINICAL ASPECTSASPECTS

CLINICAL CLINICAL ASPECTSASPECTS

• Differences from schizophrenia:Differences from schizophrenia:– preponderance of purely delusional statespreponderance of purely delusional states– preservation of warm affect preservation of warm affect – predominance of visual hallucinationspredominance of visual hallucinations

Peri-ictal psychoses

Interictal psychoses

ictal post-ictal : 25% of EP

Schizophrenia-like psychoses of epilepsy

SLPESLPE

Torta e Keller, Epilepsia 1999Torta e Keller, Epilepsia 1999

Sintomi psicotici nella MdPSintomi psicotici nella MdPSintomi psicotici nella MdPSintomi psicotici nella MdP

deplezione DA e 5HTdeplezione DA e 5HT PatogenesiPatogenesi

Up-regulation recettorialeUp-regulation recettoriale

compensatoriacompensatoria

terapia terapia DAergicaDAergica

SintomiSintomi

psicoticipsicotici

mesocorticalmesomeso

corticalcortical

5HT5HT5HT DADADAmeso

limbicmesomeso

limbiclimbic

5HT5HT5HT DADADA

5HT5HT5HT DADADAnigro

striatalnigronigro

striatalstriatal

Flush-outFlush-out5HT5HT

InterferonInterferon

Interferon(esogeno-endogeno)

Citokine(TNF-α; IL-1β; IL-6)

Asse HPA(CRH, ACTH, cortisolo)

Overlap of Mood Disorders and Psychotic Overlap of Mood Disorders and Psychotic DisordersDisorders

Depression

Psychosis Bipolar Disorder

Treatment- Resistant

Depression

Bipolar Depression

Depression with Psychotic

Features

2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition, Text Revision. Washington, DC. American Psychiatric Association, 2000.

Psychological factors

Physiological and physiological factors

Environmental factors

Cultural factors

Biopsychosocial modelBiopsychosocial model

MindMindMindMind

BrainBrainBrainBrain

WorldWorldWorldWorldBodyBodyBodyBody

Increase of mortality rate in patients with somatic diseases and mood depression

• Hypertension Hypertension • StrokeStroke• DiabetesDiabetes• Cardiovasc. dis.Cardiovasc. dis.• CancerCancer

DD

DD

DD

DD

DD

2,27 x2,27 x

3,00 x3,00 x

3,84 x3,84 x

4,04 x4,04 x

4,46 x4,46 x

Black & Markides,1999Black & Markides,1999

range of increase of mortality

DepressionDepressionDepressionDepression

Mortality increaseMortality increaseMortality increaseMortality increase

PLT’s hyperaggregationPLT’s hyperaggregationPLT’s hyperaggregationPLT’s hyperaggregation

Behavioural factorsBehavioural factorsBehavioural factorsBehavioural factors

HPA hyperactivityHPA hyperactivityHPA hyperactivityHPA hyperactivity

? Immunological Immunological alterationsalterations

Immunological Immunological alterationsalterations

Reduced HRVReduced HRVReduced HRVReduced HRV

smoking therapeutic compliance

dietphysical activity • obesity

• hyperglycemia• dyslipidemia• hypertension

Joynt et al, Biol Psychiatry, 54, 2003

ADs?

Mood depressionMood depression

BIOLOGICAL BASISBIOLOGICAL BASIS

neurotrasmettitorialneurotrasmettitorial

hormonalhormonal

immunologicalimmunological

neurotrophicneurotrophic

5HT - NE- DA5HT - NE- DA

HPA - HPTHPA - HPT

NK - ILNK - IL

BDNF - NGFBDNF - NGF

Stress hormons and AntidepressantsTreatment with antidepressantsTreatment with antidepressants

1- De Bellis et al, 19991- De Bellis et al, 19992- Reul et al.,19932- Reul et al.,1993

Normalization of HPA axis activityNormalization of HPA axis activity

SSRISSRI NSRINSRI

MAOIMAOINRINRI

< CRH and AVP concentrations < CRH and AVP concentrations 11

> GR > GR ss gene expression gene expression 22

> corticosteroid brain binding > corticosteroid brain binding 22

Clinical improvementClinical improvement

pro-inflammatory pro-inflammatory cytokinescytokines

NO/PGE2NO/PGE2

CRH activation CRH activation

IDO inductionIDO induction

HPA hyperactivity

neurotransmitters modifications

depressive symptomsdepressive symptoms

Physiological Factors Physiological Factors

IFNIFNtryptophan depletion

reduced 5HT availability

++

--

anti-inflammatory anti-inflammatory cytokinescytokines

ADsADs--

antidepressants immunomodulatory effectsantidepressants immunomodulatory effects

decrease in the pro-inflammatory cytokine IL-12 increase in the antiinflammatory cytokine TGF-β1

Effects of antidepressants Effects of antidepressants after chronic administration after chronic administration

nucleusnucleus

ReceptorReceptor

BDNFBDNFNGFNGF

neurotrasnmitters neurotrasnmitters releaserelease

receptors down receptors down regulation regulation

effectoreffector

regulation of regulation of transductional transductional mechanismsmechanisms

Protein kinaseProtein kinaseControl of genic expression Control of genic expression (neurotrophic hypothesis) (neurotrophic hypothesis)

ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGS


hormonalhormonal




HPA - HPTHPA - HPT

NK - ILNK - IL


painpain

stressstress

moodmood

anxietyanxiety

ADsADs

Atypical Antipsychotics

N OON

N

H

Cl

Cl

Aripiprazole

N

O

Cl

N

N

SN

H

N

N CH3

N

O

ON

F

Risperidone Ziprasidone

N

N

N

N

C l

C H3

N

N S

N

N

C H3

C H3

N

S

N

N

OO H

Olanzapine Clozapine Quetiapine

MARTAMARTAMARTAMARTA

SDASDASDASDA

Profilo di legame al recettore di antipsicotici

Bymaster et al. Neuropsychopharmacology. 1996;14:87–96Seeger et al. J Pharmacol Exp Ther. 1995;275:101–113

Daniel et al. 1999; Arnt and Skarsfeld, 1998. Informazioni sulla prescrizione di Abilify®

Recettore per Aripiprazolo

(Abilify®)Olanzapina(Zyprexa®)

Risperidone (Risperdal®)

Quetiapina(Seroquel®)

Ziprasidone(Geodon®)

Clozapina(Clozaril®)

Aloperidolo(Haldol®)

D1 265* 31 430 455 525 85 210

D2 0,34* 11 4 160 5 126 0,7

D3 0,8* 49 10 340 7 473 2

D4 44* 27 9 1600 32 35 3

5-HT1A 1,7* >10.000 210 2.800 3 875 1.100

5-HT2A 3,4* 4 0,5 295 0,4 16 45

5-HT2C 15* 23 25 1.500 1 16 >10.000

1 57 19 0,7 7 11 7 6

H1 61* 7 20 11 50 6 440

M1 >10.000 1,9 >10.000 120 >1.000 1,9 >1.500

Dati espressi come Ki (nM) *Dati relativi a recettori umani clonati

painpain

stressstress

moodmood

psychosespsychoses

APsAPs


hormonalhormonal




HPA - HPTHPA - HPT

NK - ILNK - IL


ANTIPSYCHOTICS ?ANTIPSYCHOTICS ?ANTIPSYCHOTICS ?ANTIPSYCHOTICS ?

??


hormonalhormonal




HPA - HPTHPA - HPT

NK - ILNK - IL



Ipotesi dopaminergica della schizofrenia

Stahl SM. Essential Psychopharmacology of antipsychotics and mood stabilizers; 1st ed. Cambridge: Cambridge University Press; 2002

Ipoattività:sintomi negativi,deficit cognitivo

Iperattività:sintomipositivi

Via mesocorticaleapprendimento e memoria

Via mesolimbicaemozioni

Via tubero-infundibulare regolazione prolattina

Via nigrostriataleregolazione del movimento

5HT5HT5HT5HT DADADADAmesomeso

corticalcortical

mesomeso

corticalcortical


limbiclimbic

mesomeso

limbiclimbic

5HT5HT5HT5HT DADADADAnigronigro

striatalstriatalnigronigro

striatalstriatal

mesomeso

corticalcortical

mesomeso

corticalcortical


limbiclimbic

mesomeso

limbiclimbic

5HT5HT5HT5HT DADADADA

5HT5HT5HT5HT DADADADAnigronigro

striatalstriatalnigronigro

striatalstriatal

Olanzapine Data Suggest Effects Olanzapine Data Suggest Effects AcrossAcross

Multiple Neurotransmittor SystemsMultiple Neurotransmittor Systems

Dopamine Direct DA receptor antagonist

DA antagonists reduce psychotic symptoms

Serotonin Multiple, balanced 5HT receptor effects

5HT may affect mood, violence, suicide

Acetylcholine May indirectly enhance ACh release

Cholinomimetics may reduce mania, improve cognition

GABA May indirectly enhance GABA release

Mood stabilizing anti-convulsants pro-GABA

SYSTEM Olanzapine Action Relevance to Bipolar

––––––

AchAch

Postsynaptic NervePostsynaptic Nerve

Presynaptic NervePresynaptic Nerve

++++

++

Ach EAch E

SerotoninSerotonin

AcetylcholineAcetylcholine MM11 MM11 MM11 MM11

AchAch

MM11

Summary Hypothesized Interaction: Summary Hypothesized Interaction: “Serotonin-Cholinergic” System“Serotonin-Cholinergic” System

Summary Hypothesized Interaction: Summary Hypothesized Interaction: “Serotonin-Cholinergic” System“Serotonin-Cholinergic” System

5HT5HT66

5HT5HT33

5HT= 5HT= AchAch

5HT5HT2A2A

5HT5HT44

5HT5HT1A1A

5HT5HT AchAch

5HT5HT2C2C

Kennedy JS et al. 2000Kennedy JS et al. 2000

Blockade:< Ach

Blockade:> Ach

Effe

ct a

t the

4 h

our t

ime

poin

t

0

100

200

300

400

500

600

**

** **

Peak Effects

Effects of Olanzapine and Other Antipsychotic Agents in Combination with Fluoxetine or Sertraline:

Extracellular Monoamine Levels in the Rat Prefrontal Cortex

Serotonin

DopamineNorepinephrine

Clozapine (3)* + Fluoxetine (10)*Risperidone (1)* + Fluoxetine (10)*Haloperidol (1)* + Fluoxetine (10)*Olanzapine (3)* + Sertraline (10)*

**P<.05 fluoxetine alone Zhang W et al.2000 * mg/kg doses.

Fluoxetine (10)*Olanzapine (3)* + Fluoxetine (10)*

To analysis

Pump 2 l/min

Microdialysisprobe

2 mm mcdls loop


hormonalhormonal




HPA - HPTHPA - HPT

NK - ILNK - IL



EpilepsyEpilepsy SeizuresSeizures

PsychosesPsychoses

antagonismantagonismagonismagonism

nerve cell lossnerve cell loss

gliosisgliosis

Sclerosis of anterior Sclerosis of anterior hippocampushippocampus

Short termShort term

agonismagonismLong termLong term

ATROPHY OF THE HUMAN HIPPOCAMPUSATROPHY OF THE HUMAN HIPPOCAMPUS

Cushing’s diseaseCushing’s disease

Major DepressionMajor Depression

Bipolar DisorderBipolar Disorder

PTSDPTSD

SchizophreniaSchizophrenia

Alzheimer DiseaseAlzheimer Disease

EpilepsyEpilepsy

Parkinson’s diseaseParkinson’s disease

tianeptine tianeptine (affects structural plasticity in hippocampus) (affects structural plasticity in hippocampus) phenytoin phenytoin (antiseizure and neuroprotective)(antiseizure and neuroprotective)fluoxetine fluoxetine (increase hippocampal neurogenesis)(increase hippocampal neurogenesis) lithium lithium (neuroprotective and antiapoptotic)(neuroprotective and antiapoptotic) tricyclic antidepressants tricyclic antidepressants (increase hippocampal neurogenesis)(increase hippocampal neurogenesis) antipsychotics antipsychotics (reduce hippocampal neuronal suppression)(reduce hippocampal neuronal suppression)sodium valproate sodium valproate (increases neurogenesis) (increases neurogenesis) mifepristone mifepristone (antioxidant, neuroprotective and anti-glucocorticoid)(antioxidant, neuroprotective and anti-glucocorticoid)

Dhikav and Anand,2007

Cultures treated with olanzapine + Ab25–35, or quetiapine +Ab25–35, had significantly higher cell viabilities and lower rates of apoptosis compared with the cultures exposed only to Ab25–35.

catecholaminescatecholaminescatecholaminescatecholamines

cytokinescytokinescytokinescytokinesneurotrophicneurotrophicfactorsfactors

neurotrophicneurotrophicfactorsfactors

chronicchronicstressstress

treatment with conventional antipsychotic drugs reduced plasma HVA level in the group of schizophrenic patients who experienced symptomatic improvement.

treatment with olanzapine for 8 weeks increased the plasma MHPG levels, which were associated with the changes in the total scores of negative symptoms on the Positive and Negative Symptom Scale (PANSS-N), and olanzapine treatment decreased the plasma HVA levels

Plasma IL-2 levels were higher in schizophrenic patients than those in normal controls and treatment with olanzapine for 8 weeks significantly decreased the plasma IL-2 levels

A range of psychiatric manifestations, including delusions, delirium, paranoia, hallucinations has been observed in patients receiving IL-2 immunotherapeutically ( Denikoff, 1987)

There was a significant inverse relationship between IL-2 level and the PANSS positive subscale P.

IL-2 increased dopamine (DA) turnover in the prefrontal cortex and stimulates the release of DA from rat striatal cells.

Elevated levels of IL-2 centrally could result in increased DA neurotransmission and therefore contribute to the clinical profile of schizophrenia and other psychoses

positive association between higher serum levels of IL-8 with negative symptoms.

Positive correlation between cortisol and negative symptoms

Risperidone, which is more effective on negative symptoms, decreased cortisol serum levels more to a greater degree than haloperidol.

Negative correlation with Negative correlation with positive symptomspositive symptoms

Photomicroscophic images of BDNF mRNA expression in rat neocortex.

Chronic administration of quetiapine attenuated the decrease in rat hippocampal BDNF levels caused by immobilization stress

(1) CRS decreased hippocampal cell proliferation and BDNF expression;(2) chronic administration of quetiapine or venlafaxine dosedependently prevented these decreases in

hippocampal cell proliferation and BDNF expression caused by CRS;(3) the combination of lower doses of quetiapine (5 mg/kg) and venlafaxine (2.5 mg/kg) increased

hippocampal cell proliferation and prevented BDNF decrease in stressed rats; (4) individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted

effects comparable to those produced by their combination.

Allopregnanolone(3-idrossi-5-pregnan-20-one)

THDOC(3,21-diidrossi-5-pregnan-20-one)

Potenziamento della trasmissione GABAergica

Effetti farmacologici

AnsioliticoAnticonvulsivanteSedativo-ipnotico

Anestetico

HOH

O

OH

HOH

O

Selective Serotonin Reuptake Inhibitors Directly Alter Activity of Neurosteroidogenic Enzymes

Griffin LD, Mellon SH Proc Natl Acad Sci U S A 1999;96(23):13512-7

3-HSD

5-riduttasi

(+)

Pregnenolone

Progesterone Diidroprogesterone

Allopregnanolone

SSRI 3-HSD

Modificata da: Griffin L, et al., 2002

Modificata da: Farrant M, et al., 2005

Peripherally secretedand locally

metabolized steroids

Mitochondrion

3,5-THP

Postsynaptic

SertralinaFluoxetinaParoxetinaDuloxetinaOlanzapinaClozapina

SertralinaFluoxetinaParoxetinaDuloxetinaOlanzapinaClozapina

Psychological factors

Physiological and physiological factors

Environmental factors

Cultural factors

Biopsychosocial modelBiopsychosocial model

MindMindMindMind

BrainBrainBrainBrain

WorldWorldWorldWorldBodyBodyBodyBody

Fig. 2. The number of new neurons in the granule cell layer (Gcl) of adult rats increases following spatial learning in the Morris water maze. Confocal laser scanning microscopic images of BrdU labeled cells (arrows) reveal a difference in number between control (a) and spatial learning (b) adult rats. The vast majority of BrdU labeled cells (arrows) had the morphology of granule neurons and were immunoreactive for the marker of immature neurons TOAD-64 (c) but not the astroglial marker GFAP (d). GFAP-positive astrocytes that are not BrdU labeled are indicated by arrowheads.

New neuron formation during learning

Gould et al. Nat Neuro 1999; 2: 260-265.

Psychotherapy produces long-term changes in behavior,presumably through learning

implicit domain of memoryunconscious, procedural

interaction with therapist

acquisition of new sets of implicit memories

explicit domain of memoryconscious, declarative

amigdalaamigdala cortexcortex

LTPLTPLong Term PotentiationLong Term Potentiation

BRAIN PHYSIOLOGY AND SCHOOLS OF PSYCHOTHERAPYBRAIN PHYSIOLOGY AND SCHOOLS OF PSYCHOTHERAPY

Behavioral psychotherapyBehavioral psychotherapy focuses on dysfunction in simple forms of learning focuses on dysfunction in simple forms of learning and memory (operant and associative conditioning) and related motor behavior. and memory (operant and associative conditioning) and related motor behavior. This paradigm involves brain structures such as the amygdala, basal ganglia, and This paradigm involves brain structures such as the amygdala, basal ganglia, and hippocampus.hippocampus.

Behavioral psychotherapyBehavioral psychotherapy focuses on dysfunction in simple forms of learning focuses on dysfunction in simple forms of learning and memory (operant and associative conditioning) and related motor behavior. and memory (operant and associative conditioning) and related motor behavior. This paradigm involves brain structures such as the amygdala, basal ganglia, and This paradigm involves brain structures such as the amygdala, basal ganglia, and hippocampus.hippocampus.

Cognitive psychotherapyCognitive psychotherapy focuses on specific patterns of information processing. focuses on specific patterns of information processing. According to cognitive theory, negative cognitions play a pivotal role in the According to cognitive theory, negative cognitions play a pivotal role in the development and maintenance of the psychopathological state. Putative brain development and maintenance of the psychopathological state. Putative brain areas include the neocortex, specifically the frontal cortex.areas include the neocortex, specifically the frontal cortex.

Cognitive psychotherapyCognitive psychotherapy focuses on specific patterns of information processing. focuses on specific patterns of information processing. According to cognitive theory, negative cognitions play a pivotal role in the According to cognitive theory, negative cognitions play a pivotal role in the development and maintenance of the psychopathological state. Putative brain development and maintenance of the psychopathological state. Putative brain areas include the neocortex, specifically the frontal cortex.areas include the neocortex, specifically the frontal cortex.

Psychodynamic psychotherapyPsychodynamic psychotherapy has as its central focus interpersonal representation: a set of has as its central focus interpersonal representation: a set of expectations about self, others, and their relationship that organizes related affect, thought, expectations about self, others, and their relationship that organizes related affect, thought, and behavior.The neuropsychological underpinnings of interpersonal representations and behavior.The neuropsychological underpinnings of interpersonal representations probably involve complex neurocircuitry incorporating lateralized cerebral hemispheres and probably involve complex neurocircuitry incorporating lateralized cerebral hemispheres and subcortical areas.subcortical areas.

Psychodynamic psychotherapyPsychodynamic psychotherapy has as its central focus interpersonal representation: a set of has as its central focus interpersonal representation: a set of expectations about self, others, and their relationship that organizes related affect, thought, expectations about self, others, and their relationship that organizes related affect, thought, and behavior.The neuropsychological underpinnings of interpersonal representations and behavior.The neuropsychological underpinnings of interpersonal representations probably involve complex neurocircuitry incorporating lateralized cerebral hemispheres and probably involve complex neurocircuitry incorporating lateralized cerebral hemispheres and subcortical areas.subcortical areas.

psychotic-like symptoms in neurological patients : beyond the dopaminergic hypothesis riccardo torta...

Documents

n n s n n

mortality slide

n n s n h n n ch

cortisolo slide

aripiprazole n o

recettori umani clonati

ht ne

ht patogenesi