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Psychotic-like symptoms in neurological patients : beyond the dopaminergic hypothesis Riccardo Torta SCDU Psicologia Clinica e Oncologica Dipartimenti.

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Presentation on theme: "Psychotic-like symptoms in neurological patients : beyond the dopaminergic hypothesis Riccardo Torta SCDU Psicologia Clinica e Oncologica Dipartimenti."— Presentation transcript:

1 Psychotic-like symptoms in neurological patients : beyond the dopaminergic hypothesis Riccardo Torta SCDU Psicologia Clinica e Oncologica Dipartimenti di Neuroscienze ed Oncologia Università di Torino Summer School of Neuroscience July 12 th, 2007

2 Psychoses Behavioural Disorders Psychoses DementiaDementia ParkinsonParkinsonEpilepsyEpilepsy nosographic problems therapeutic problems BPSD Euphoria - Psycoses SLPE Drug induced Hallucinosis MSMS

3 Brain metabolism in dementia: relationship to emotional symptomatology Sultzer DL. et al 1996 Galynker et al., 2000 Agitation/ disinhibition Psychosis Delusional thoughts (hypometabolism) Temporal Subjective mood symptoms High Low Anterior cingulate Frontal Prefrontal Frontal Parietal pole Anxiety/depression Apathy

4 BPSDBPSD NeurolepticsNeuroleptics AED as Mood stabilizers stabilizers Beta-blockersBeta-blockers Serotoninergic drugs BenzodiazepinesBenzodiazepines Atypical antipsychotics R.Torta, E. Badino, A. Scalabrino THERAPEUTIC STRATEGIES FOR BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS IN DEMENTED PATIENTS Arch Gerontol Geriatr. 2004

5 CLINICAL ASPECTS Differences from schizophrenia:Differences from schizophrenia: –preponderance of purely delusional states –preservation of warm affect –predominance of visual hallucinations Peri-ictal psychoses Interictal psychoses ictal post-ictal : 25% of EP Schizophrenia-like psychoses of epilepsy SLPE Torta e Keller, Epilepsia 1999

6 Sintomi psicotici nella MdP deplezione DA e 5HT Patogenesi Up-regulation recettoriale compensatoria compensatoria terapiaDAergica Sintomi psicotici psicotici Flush-out5HT

7 Interferon Interferon (esogeno-endogeno) Citokine (TNF-α; IL-1β; IL-6) Asse HPA (CRH, ACTH, cortisolo)

8 Overlap of Mood Disorders and Psychotic Disorders 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.

9 Psychological factors Physiological and physiological factors Environmental factors Cultural factors Biopsychosocial model MindMind BrainBrain WorldWorldBodyBody


11 Increase of mortality rate in patients with somatic diseases and mood depression HypertensionHypertension StrokeStroke DiabetesDiabetes Cardiovasc. dis.Cardiovasc. dis. CancerCancer DD 2,27 x 3,00 x 3,84 x 4,04 x 4,46 x Black & Markides,1999 range of increase of mortality

12 DepressionDepression Mortality increase PLTs hyperaggregation Behavioural factors HPA hyperactivity ? Immunological alterations Reduced HRV smoking therapeutic compliance diet physical activity obesity hyperglycemia dyslipidemia hypertension Joynt et al, Biol Psychiatry, 54, 2003 ADs?

13 Mood depression 5HT - NE- DA HPA - HPT NK - IL BDNF - NGF


15 Stress hormons and Antidepressants Treatment with antidepressants 1- De Bellis et al, 1999 2- Reul et al.,1993 Normalization of HPA axis activity SSRINSRIMAOI NRI < CRH and AVP concentrations 1 > GR s gene expression 2 > corticosteroid brain binding 2 Clinical improvement


17 pro-inflammatory cytokines NO/PGE2 CRH activation IDO induction HPA hyperactivity neurotransmitters modifications depressive symptoms Physiological Factors IFN IFN tryptophan depletion reduced 5HT availability + - anti-inflammatory cytokines ADs -


19 antidepressants immunomodulatory effects decrease in the pro-inflammatory cytokine IL-12 increase in the antiinflammatory cytokine TGF-β1


21 Effects of antidepressants after chronic administration nucleus Receptor BDNFNGF neurotrasnmitters release receptors down regulation effector regulation of transductional mechanisms Protein kinase Control of genic expression (neurotrophic hypothesis)



24 ADs anxiety mood stress pain

25 Atypical Antipsychotics N O O N N H Cl Aripiprazole N O Cl N N S N H N N CH 3 N O O N F RisperidoneZiprasidone N N N N C l C H 3 N N S N N 3 3 N S N N O O H OlanzapineClozapineQuetiapineMARTAMARTA SDASDA

26 Profilo di legame al recettore di antipsicotici Bymaster et al. Neuropsychopharmacology. 1996;14:87–96 Seeger 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 ® ) D1D1 265* 31 430 45552585210 D2D2 0,34*11 4 16051260,7 D3D3 0,8*49 1034074732 D4D4 44*27 9160032353 5-HT 1A 1,7*>10.000 210 2.80038751.100 5-HT 2A 3,4*4 0,5 2950,41645 5-HT 2C 15*23 251.500116>10.000 1 5719 0,7 71176 H1H1 61*7 20 11506440 M1M1 >10.0001,9>10.000 120>1.0001,9>1.500 Dati espressi come K i (nM) *Dati relativi a recettori umani clonati

27 APs psychoses mood stress pain


29 neurotrasmettitorial hormonal immunological neurotrophic 5HT - NE- DA HPA - HPT NK - IL BDNF - NGF ANTIPSYCHOTICS ? ?

30 neurotrasmettitorial hormonal immunological neurotrophic 5HT - NE- DA HPA - HPT NK - IL BDNF - NGF ANTIPSYCHOTICS ?

31 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: sintomi positivi Via mesocorticale apprendimento e memoria Via mesolimbica emozioni Via tubero-infundibulare regolazione prolattina Via nigrostriatale regolazione del movimento

32 5HT5HTDADA mesocorticalmesocortical 5HT5HTDADA mesolimbicmesolimbic 5HT5HTDADA nigrostriatalnigrostriatal

33 mesocorticalmesocortical 5HT5HTDADA mesolimbicmesolimbic 5HT5HTDADA 5HT5HTDADA nigrostriatalnigrostriatal

34 Olanzapine Data Suggest Effects Across Multiple 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 SYSTEMOlanzapine ActionRelevance to Bipolar

35 – – – Ach Postsynaptic Nerve Presynaptic Nerve + + + Ach E Serotonin Acetylcholine M1M1M1M1 M1M1M1M1 M1M1M1M1 M1M1M1M1 Ach M1M1M1M1 Summary Hypothesized Interaction: Serotonin-Cholinergic System 5HT 6 5HT 3 5HT= Ach 5HT 2A 5HT 4 5HT 1A 5HT Ach 5HT 2C Kennedy JS et al. 2000 Blockade: < Ach Blockade: > Ach

36 Effect at the 4 hour time point ** Peak Effects Effects of Olanzapine and Other Antipsychotic Agents in Combination with Fluoxetine or Sertraline: Extracellular Monoamine Levels in the Rat Prefrontal Cortex Serotonin Dopamine Norepinephrine 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 Microdialysis probe 2 mm mcdls loop

37 neurotrasmettitorial hormonal immunological neurotrophic 5HT - NE- DA HPA - HPT NK - IL BDNF - NGF ANTIPSYCHOTICS ?


39 Epilepsy Seizures Psychoses antagonismagonism nerve cell loss gliosis Sclerosis of anterior hippocampus Short term agonism Long term

40 ATROPHY OF THE HUMAN HIPPOCAMPUS Cushings disease Major Depression Bipolar Disorder PTSDSchizophrenia Alzheimer Disease Epilepsy Parkinsons disease

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

42 Dhikav and Anand,2007



45 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.

46 catecholaminescatecholamines cytokinescytokines neurotrophic factors chronicstress

47 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

48 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

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

50 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

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


53 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.

54 Negative correlation with positive symptoms


56 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

57 (1) (1)CRS decreased hippocampal cell proliferation and BDNF expression; (2) (2)chronic administration of quetiapine or venlafaxine dosedependently prevented these decreases in hippocampal cell proliferation and BDNF expression caused by CRS; (3) (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) (4)individual higher doses of quetiapine (10 mg/kg) or venlafaxine (5 mg/kg) exerted effects comparable to those produced by their combination.

58 Allopregnanolone (3 -idrossi-5 -pregnan-20-one) THDOC (3,21-diidrossi-5 -pregnan-20-one) Potenziamento della trasmissione GABAergica Effetti farmacologici Ansiolitico Anticonvulsivante Sedativo-ipnotico Anestetico HO H O OH HO H O

59 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 ProgesteroneDiidroprogesterone Allopregnanolone SSRI 3 -HSD Modificata da: Griffin L, et al., 2002

60 Modificata da: Farrant M, et al., 2005 Peripherally secreted and locally metabolized steroids Mitochondrion 3,5 -THP Postsynaptic Sertralina Fluoxetina Paroxetina Duloxetina Olanzapina Clozapina Sertralina Fluoxetina Paroxetina Duloxetina Olanzapina Clozapina



63 Psychological factors Physiological and physiological factors Environmental factors Cultural factors Biopsychosocial model MindMind BrainBrain WorldWorldBodyBody

64 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.



67 Psychotherapy produces long-term changes in behavior, presumably through learning implicit domain of memory unconscious, procedural interaction with therapist acquisition of new sets of implicit memories explicit domain of memory conscious, declarative amigdala cortex LTP Long Term Potentiation

68 BRAIN PHYSIOLOGY AND SCHOOLS OF PSYCHOTHERAPY Behavioral psychotherapy focuses on dysfunction in simple forms of learning and memory (operant and associative conditioning) and related motor behavior. This paradigm involves brain structures such as the amygdala, basal ganglia, and hippocampus. Cognitive psychotherapy focuses on specific patterns of information processing. According to cognitive theory, negative cognitions play a pivotal role in the development and maintenance of the psychopathological state. Putative brain areas include the neocortex, specifically the frontal cortex. Psychodynamic psychotherapy has as its central focus interpersonal representation: a set of expectations about self, others, and their relationship that organizes related affect, thought, and behavior.The neuropsychological underpinnings of interpersonal representations probably involve complex neurocircuitry incorporating lateralized cerebral hemispheres and subcortical areas.

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