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

11.05 ד"ר יהודה ברוךמנהל המרכז לבריאות הנפש ע"ש י.

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Schizophrenia

28/11/05


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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.


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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.


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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.

What is schizophrenia?What is schizophrenia?


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Two categories of symptoms in schizophrenia:

• Positive symptoms

• Negative symptoms


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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


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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).


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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


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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


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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.”


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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


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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


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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


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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


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Disorganized Motor Disturbances

• Extreme activity levels (unusually high or low), peculiar body movements or postures (e.g., catatonic schizophrenia), strange gestures and grimaces


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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


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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


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• 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


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• 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.


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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


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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.

• 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

• 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.


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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


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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


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Structural changes in brain

• Larger ventricles– Subgroup: inverse correlation between

ventricle size and response to drugs


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• 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


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• Increased loss of gray matter in adolescence


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• 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


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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


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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


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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.


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Neurotransmitter involved in 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.

Dopamine-hypothesis of schizophrenia

(Freedman 2003 N Engl J Med 349:1738)


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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.


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• Altered activity of GAD and altered expression of GAT1 and GABAR subunits in prefrontal cortex and hippocampus in brains from schizophrenic patients.


• Enhancing GABAergic function, primarily through the use of benzodiazepines, has not yielded convincing results of specific effects in schizophrenia.

GABA

Relation to disruption of neuronal migration during cortex development?


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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


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Glutamate hypothesis

• Problem with DA hypothesis: time course

• Phencyclidine (PCP): dissociative anesthetic – Auditory hallucinations– Depersonalization– Delusions– Noncompetitive NMDA antagonist (blocks

Ca2+ channel)


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• Altered activity of GAD and altered expression of GAT1 and GABAR subunits in prefrontal cortex and hippocampus in brains from schizophrenic patients.


• Enhancing GABAergic function, primarily through the use of benzodiazepines, has not yielded convincing results of specific effects in schizophrenia.

GABA

Relation to disruption of neuronal migration during cortex development?


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Glutamate-hypothesis of schizophreniaClinical 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)


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• 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?????


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• 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.

Dopamine-Glutamate interactions

• 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..


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Implications of Glu hypofunction for schizophrenia

(Konradi & Heckers 2003 Pharm & Ther 97: 153)

Glu is involved in early synapse

formation and stabilisation

A hypoactive system leadsto sparse neuronal circuits


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• Seizures!! (also excitotoxicity)

• Try mGluR agonists: 8 subtypes of mGluR– Some modulate glutamate release– Others modulate dopamine systems


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Genes for schizophrenia

(Harrison & Owen 2003 The Lancet 361: 417)

• Recent genetic linkage studies have identified candidate susceptibility genes for schizophrenia.

• 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.


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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 subunit)Calcineurin k.o. mice display behavioural abnormalities reminiscent of altered behaviour observed in schizophrenic patients.

Finding needs replication in largerand more diverse sample size

• GRIN1 (encoding NR1 subunit of NMDARs)

• GRM3 (encoding mGluR3 receptors)


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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.


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Neuregulin-1/erbB signalling and schizophrenia

(Corfas et al 2004 Nature Neuroscience 7: 575)


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• G72 primate specific gene encodes a 153 aa protein that interacts with DAAO (D-amino acid oxidase) resulting in the activation of the enzyme.

Genes for schizophrenia:DAAO and G72

• 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.


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Metabolic pathway for D-serine

DAAO

Serine Racemase

Serine Transporter

Serine Transporter


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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, 1, H1, m1/4)


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