Schizophrenia

Famous schizophrenics:

HölderlinMaupassantLenzWalser, RobertProustStrindbergLenau

Prevalence

1 % throughout the world

Time course

Begins during young adulthood:

in males 21-25 yearsin females 28-32 years

Generally progressive (if untreated)

Begins withPositive symptoms after years negative symptoms dominate

Positive symptoms

Disordered thoughtsDelusions (f.e. the belief that one is being persecuted or that one‘s feelings, thoughts and actions are controlled by an outside forceHallucinations, usually auditory hearing voices commenting on one‘s actions

Negative symptoms

Loss of normal association between ideas, incoherence of ideasPoverty of speechFlattening, loss, or iadequate affectSocial withdrawal

Causes

Genetic disposition/vulnerability

Two hit hypothesis:

50% genetic 50 % second hit ???

Second hit: Birth hypoxia Stress Cannabis use Psychostimulant use

Morphological findings

Enlargement of the 3rd ventricle

Reduced volume of the corpus callosum ???

Disturbed layerd arrangement of Hippocampus??? prefront. Cortex???

Neurochemical findings

Dopamine hypothesis:

A Dopamine hyperactivity underlies the disease

Regional selectivity hypothesis:Dopamine hyperactivity in the meso-accumbal/limbic systemDopamine hypoactivity in the prefrontal cortex

Glutamate hypothesis:

A Glutamate hypoactivity underlies the disease

Behavioural pharmacology

Animal models of Schizophrenia:

Pharmacological induction of dopamine hyperactivity

Pharmacological induction of glutamate hypoactivity

Developmental models

Genetic models (breeding the endophenotype)

Typical antipsychotics

Chlorpromazine, HaloperidolEffect:block DA receptors; counteract mainly positive symptomsSideeffects: Parkinsonism

Atypical antipsychotics

Clozapine, Olanzapine, Sertindole, Effect: Receptor? counteract positive and negative symptoms/depressionSide effects: No parkinsonism

New generationAripiprazolPartial Dopamine agonists: Anatgonists in n. accumbens Agonists in prefront. cortex

Psychostimulant-induced psychosis

…the psychosis that arises from repeated administration of cocaine or amphetamine results from sensitization…(Robinson and Becker 1986)

A role for sensitization in psychostimulant-induced Paranoia and psychosis(Kalivas et al. Mojacar meeting 1998)

1. The development of psychostimulant psychosis requires a prolonged period of abuse in nonschizophrenic individuals.2. Relapse psychosis can occur following reexposure to a lower dose of drug than that associated with initial psychosis.3. Sensitivity to drug-induced psychosis persists even after years of abstinence, indicating enduring psychostimulant-induced changes in neural function.

Schizophrenia and sensitization

Dysregulated dopamine/glutamate balance

Attribution of aberrant salience to stimuli,Aberrant sense of novelty

Delusions to explain the aberrant salience

Antipsychotics block dopamine receptors within hours

Dampening of salience of encountered stimuliby way of desensitization/unlearning saliencewithin some weeks