מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל
Schizophrenia 28/11/05 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

A bit of history Hideyo Noguchi, 1911: Syphillis (delusions, grandiosity, impulsivity, altered thought structure) is due to bacterium. Emil Kraeplin, 1919: dementia praecox (paranoia, grandiose delusions, auditory hallucinations, abnormal emotional reg., bizarre thoughts)—partly genetic Eugen Bleuler, 1911: key is dissociative thinking; also delusions, hallucinations, affective disturbance, autism. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Schizophrenia actually refers to a group of disorders. There is not one essential symptom that must be present for a diagnosis. Instead, patients experience different combinations of the main symptoms of schizophrenia. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

What is schizophrenia? Schizophrenia actually refers to a group of disorders. There is not one essential symptom that must be present for a diagnosis. Instead, patients experience different combinations of the main symptoms of schizophrenia. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Two categories of symptoms in schizophrenia:
Positive symptoms Negative symptoms 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Positive Symptoms Distortions or excesses of normal functioning (e.g., delusions, hallucinations, disorganized speech/thought disturbances, motor disturbances) Positive symptoms are generally more responsive to treatment than negative symptoms 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Delusions False beliefs that are firmly and consistently held despite disconfirming evidence,culture or logic. Individuals with mania or delusional depression may also experience delusions. However, the delusions of patients with schizophrenia are often more bizarre (highly implausible). 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Types of delusions Delusions of persecution: belief that one is the target of others’ mistreatment, evil plots, and/or murderous intent (most common) Delusions of reference: belief that all happenings revolve around oneself, and/or one is always the center of attention 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Types of delusions Delusions of grandeur: belief that one is a famous or powerful person from the past or present Delusions of control: belief that some external force is trying to take control of one’s thoughts (thought insertion), body, or behavior 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Example of delusions of control Thought insertion = Believing that thoughts that are not your own have been placed in your mind by an external source A 29-year-old housewife said, “I look out of the window and I think the garden looks nice and the grass looks cool, but the thoughts of Eamonn Andrews come into my mind. There are no other thoughts there, only his… He treats my mind like a screen and flashes his thoughts on it like you flash a picture.” 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Types of delusions Thought broadcasting: belief that one’s thoughts are being broadcast or transmitted to others Thought withdrawal: belief that one’s thoughts are being removed from one’s mind 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Hallucinations Sensory experiences in the absence of any stimulation from the environment Any sensory modality may be involved: auditory (hearing); visual (seeing); olfactory (smelling); tactile (feeling); gustatory (tasting) Auditory hallucinations are most common 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Common auditory hallucinations in schizophrenia
Hearing own thoughts spoken by another voice Hearing voices that are arguing Hearing voices commenting on one’s own behavior 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Disorganized Speech / Thought Disturbances
Problems in organizing ideas and speaking so that a listener can understand Loose Associations (cognitive slippage): continual shifting from topic to topic without any apparent or logical connection between thoughts Neologisms: new, seemingly meaningless words that are formed by combining words 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Disorganized Motor Disturbances
Extreme activity levels (unusually high or low), peculiar body movements or postures (e.g., catatonic schizophrenia), strange gestures and grimaces 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Negative Symptoms Behavioral deficits that endure beyond an acute episode of schizophrenia More negative symptoms are associated with a poorer prognosis Some negative symptoms might be secondary to medications and/or institutionalization 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Types of negative symptoms
Anhedonia: inability to feel pleasure; lack of interest or enjoyment in activities or relationships Avolition: inability or lack of energy to engage in routine (e.g., personal hygiene) and/or goal-directed (e.g., work, school) activities 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Alogia: lack of meaningful speech, which may take several forms, including poverty of speech (reduced amount of speech) or poverty of content of speech (little information is conveyed; vague, repetitive) Asociality: impairments in social relationships; few friends, poor social skills, little interest in being with other people 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Flat affect: no stimulus can elicit an emotional response. Patient may stare vacantly, with lifeless eyes and expressionless face. Voice may be toneless. Flat affect refers only to outward expression, not necessarily internal experience. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Schizophrenia Subtypes (DSM-IV)
Paranoid Type: preoccupation with one or more delusions or frequent auditory hallucinations Disorganized Type: disorganized speech, disorganized behavior, and flat or inappropriate affect Catatonic Type: motoric immobility or excessive motor activity, extreme negativism or mutism, peculiar voluntary movement, echolalia or echopraxia Undifferentiated Type: none of the above Residual Type: Absence of prominent delusions, hallucinations, disorganized speech/behavior but odd beliefs/behavior or negative symptoms Echolalia is the repetition or echoing of verbal utterances made by another person. Echopraxia is the involuntary imitation of movements of another person. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

What causes schizophrenia?
There is no one accepted cause for schizophrenia. Interactions between genetic predisposition and environmental influences disrupt neurodevelopmental processes leading first to pre-morbid symptoms and then to the onset and progression of schizophrenia. Heredity  schizophrenia is genetically linked  more than one gene may predispose people to it  there is currently no reliable way to predict whether a person will develop the disease. Environment  pregnancy and delivery complications  childhood and prenatal virus infection  urban birth and residence  psychosocial factors (dysfunctional family environment) Changes in brain structure  enlarged ventricles  reduced regional cerebral volumes  reduced activity in the temporal lobes 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Twin studies Why does one twin become schizophrenic and the other does not? Lower birth weight More physiological distress More submissive, tearful, sensitive Impaired motor coordination 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Genes Genes scattered across all but 8 chromosomes have been implicated Most important: Neuregulin 1: NMDA, GABA, & Ach receptors Dysbindin: synaptic plasticity Catechol-O-methyl transferase: DA metabol. G72: regulates glutamatergic activity Others: myelination, glial function Paternal age: more cell divisions in sperm 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Structural changes in brain
Larger ventricles Subgroup: inverse correlation between ventricle size and response to drugs 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Hippocampus, amygdala, parahippocamp. Smaller in affected twin (static trait) Disordered hippocampal pyramidal cells Correlation between cell disorder and severity May be due to maternal influenza in 2nd trimester Also in entorhinal, cingulate, parahippocampal cortex 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Increased loss of gray matter in adolescence 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Shrinkage of cerebellar vermis Thicker corpus callosum Frontal lobes Abnormal neuronal migration in one study Dendrites have fewer spines But no major structural abnormalities Measures of frontal function impaired 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Functional changes in brain
Hypofrontality hypothesis Discordant twins: low frontal blood flow only in affected twin Wisconsin card sorting task Schizophrenics can’t shift attn. to other criterion Functional imaging: frontal lobe activity lower at rest, esp. in right hemisphere, does not increase during task. Drug treatment increased activation of frontal lobes 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Neurochemical changes
LSD, mescaline  confusion, delirium, disorientation, visual hallucinations. But schizophrenic hallucinations are mostly auditory Schizophrenics given LSD say it’s different from their symptoms 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Dopamine hypothesis Amphetamine (very high doses)  paranoia, delusions, auditory hallucination Also exacerbates symptoms of schiz. Effects blocked by DA antagonist chlorpromazine Phenothiazines (incl. chlorprom.) & all other typical neuroleptics block D2 receptors and alleviate (+) symptoms. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Neurotransmitter involved in schizophrenia
Dopamine-hypothesis of schizophrenia Clinical observations: Conventional antipsychotic drugs inhibit D2 receptor. Schizophrenia-like symptoms occur in amphetamine abusers, due to excessive DA release. Baseline DA levels and stimulated release of DA are abnormal in mesolimbic systems of brains from schizophrenic patients.  DA system plays a role in schizophrenia. However, it is likely not to be the only and/or main neurotransmitter system implicated. (Freedman 2003 N Engl J Med 349:1738) 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Serotonin 5HT has been implicated in a variety of schizophrenia symptoms (e.g. hallucinations, cognitive dysfunction, sensory gating, aggression) Atypical antipsychotic have relatively high affinity for 5HT2 receptors. Blocking of 5HTRs may be a requirement for the reduction in extrapyramidal symptoms. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

GABA Clinical observations: Enhancing GABAergic function, primarily through the use of benzodiazepines, has not yielded convincing results of specific effects in schizophrenia. Altered activity of GAD and altered expression of GAT1 and GABAR subunits in prefrontal cortex and hippocampus in brains from schizophrenic patients. Relation to disruption of neuronal migration during cortex development? 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Atypical neuroleptics
Clozapine blocks 5-HT2A receptors > D2 As effective as typical neuroleptics on (+) symptoms, more effective on (-) symptoms Fewer motor side effects (tardive dyskinesia) Actually increase DA release in frontal cortex L-DOPA can even be beneficial 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Glutamate hypothesis Problem with DA hypothesis: time course Phencyclidine (PCP): dissociative anesthetic  Auditory hallucinations Depersonalization Delusions Noncompetitive NMDA antagonist (blocks Ca2+ channel) 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

GABA Clinical observations: Enhancing GABAergic function, primarily through the use of benzodiazepines, has not yielded convincing results of specific effects in schizophrenia. Altered activity of GAD and altered expression of GAT1 and GABAR subunits in prefrontal cortex and hippocampus in brains from schizophrenic patients. Relation to disruption of neuronal migration during cortex development? 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Glutamate-hypothesis of schizophrenia Clinical observations: PCP and ketamine cause schizophrenia-like psychoses and cognitive deficits in normal subjects and worsens the symptoms of schizophrenia in patients. Gly site agonists improve outcome of treatment in schizophrenia. Sarcosine reduces symptoms in chronic schizophrenics under neuroleptic treatment. AMPA receptor potentiators administered on medicated patients improve performance in attention, memory and distractability tests. Significant reduction in CSF Glu levels in schizophrenic subjects. iGluR but not mGluR subunit expression is altered in hippocampus, thalamus and cortex) 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Glutamate hypothesis 2 weeks PCP in monkeys  schiz.-like symptoms Including poor performance on frontal lobe-sensitive task Dose- & time-sensitive Ketamine (NMDA antag) similar effects So, why not give glutamate agonists to treat schizophrenia????? 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Dopamine-Glutamate interactions
DA neurones in the substantia nigra and VTA receive glutamatergic inputs and Glu stimulates DA activity. Conversely, the glutamate system is inhibited by DA and D2R antagonists reverse the inhibition. D2 receptors also reduce GluR-mediated activity in corticostriatal and thalamostriatal pathways, while D2 antagonists increase the activity. In the striatum, an intracellular interaction between D2 and NMDA receptors induces increased NMDAR activity. Acute treatment with NMDAR antagonists increases DA release in the PFC and sub-cortical structures (in vivo dialysis). Chronic treatment with NMDAR antagonists results in decreased DA release in the PFC but not subcortical structures (in vivo dialysis, turnover measurements). Modulation of the DA system by antipsychotic drugs influences the performance of the Glu system. Altered function of the Glu system affects the performance of the DA system.. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Implications of Glu hypofunction for schizophrenia
Glu is involved in early synapse formation and stabilisation A hypoactive system leads to sparse neuronal circuits (Konradi & Heckers 2003 Pharm & Ther 97: 153) 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Glutamate hypothesis Seizures!! (also excitotoxicity) Try mGluR agonists: 8 subtypes of mGluR Some modulate glutamate release Others modulate dopamine systems 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Genes for schizophrenia
Recent genetic linkage studies have identified candidate susceptibility genes for schizophrenia. (Harrison & Owen 2003 The Lancet 361: 417) The modulation of excitatory transmission and in particular of NMDAR function appears to be the common link among most recently described susceptibility genes for schizophrenia. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Genes for schizophrenia
RGS4 (regulator of G protein function) RGS4 inhibits signalling by the mGluR5, which stimulation potentiates NMDA-mediated currents. DTNBP1 (encoding dysbindin-1) Protein levels are significantly reduced in the hippocampal formation of schizophrenic individuals. However, patients with dysbindin mutations do not show symptoms of schizophrenia. PPP3CC (encoding calcineurin g subunit) Calcineurin k.o. mice display behavioural abnormalities reminiscent of altered behaviour observed in schizophrenic patients. Finding needs replication in larger and more diverse sample size GRIN1 (encoding NR1 subunit of NMDARs) GRM3 (encoding mGluR3 receptors) 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Genes for schizophrenia:
NRG1 Neuregulin1: cell-cell signalling protein containing an epidermal growth factor (EGF)-like motif that bind to membrane-associated Tyr kinases of the erbB family. NRG1 regulates expression of GluR subunits. NRG1 is colocalised with the NMDAR and modulates its kinetic properties by phosphorylation of the NR2 subunit. NRG-1 mRNA is increased in brains from schizophrenic patients. Significant reduction in the level of erbB3 expression in brains from schizophrenic patients. Mice heterozygous for mutations in the NRG1 gene display hyperactivity in behavioural tests similar to that observed in PCP treated mice. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Neuregulin-1/erbB signalling and schizophrenia
11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל (Corfas et al 2004 Nature Neuroscience 7: 575)

Genes for schizophrenia:
DAAO and G72 G72 primate specific gene encodes a 153 aa protein that interacts with DAAO (D-amino acid oxidase) resulting in the activation of the enzyme. DAAO is responsible for the catabolism of D-serine. DAAO is heterogeneously distributed in the brain. Brainstem and cerebellum are richer in enzyme levels than forebrain regions. DAAO is prevalent in astrocytes and glial cells, although some studies suggest that enzyme can be localised also in neurones. Subcellular localisation of DAAO appears to be peroxisomal. 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Metabolic pathway for D-serine
DAAO Serine Racemase Serine Transporter 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

How is schizophrenia treated?
There is currently no cure for schizophrenia. Treatment is aimed at reducing symptoms and preventing psychotic relapses. Medication needs to be continue. Two major types of antipsychotic medications (or neuroleptics): CONVENTIONAL or TYPICAL ANTIPSYCHOTICS (haloperidol)  control the positive symptoms very effectively  side effects: extrapyramidal symptoms (chronic: tardive dyskinesia, parkinsonism, akathisia; acute: acute dystonia, neuroleptic malignant syndrome)  high affinity for D2 dopamine receptors NEWER or ATYPICAL ANTIPSYCHOTICS (clozapine, risperidone, olanzapine, ziprasidone, quietapine, sertindole)  better at treating the negative symptoms  milder motor side effects; but others (weight gain, diabetes)  they have affinity to multiple receptor systems (DARs, 5HTRs, a1, H1, m1/4) 11.05 ד"ר יהודה ברוך מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Similar presentations

Presentation on theme: "מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל

Similar presentations

Presentation on theme: "מנהל המרכז לבריאות הנפש ע"ש י. אברבנאל"— Presentation transcript:

Similar presentations

About project

Feedback