Schizophrenia

Positive symptoms

* Make themselves known by their presence – excess
* Including thought disorders, delusions and hallucinations 
* **Thought disorders** → disorganized and irrational thinking
* **Delusions** → beliefs that are contrary to fact. Many types (persecution, grandeur, control)

**Hallucinations** →perceptions of stimuli that aren’t actually there → auditory ones are most common, so are olfactory ones

Negative symptoms

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* Flattened emotional response
* Poverty of speech 
* Lack of initiative 
* Persistence
* Anhedonia
* Social withdrawal

Cognitive symptoms

* Difficulty in sustaining attention
* Low psychomotor speed
* Deficits in learning and memory 
* Poor abstract thinking and problem-solving 

→ all neurocognitive deficits are associated with frontal lobe dysfunction 

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→ Weinberger 1988: negative symptoms are caused by hypofrontality

Stroop task

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* schizophrenia patients are slower and less accurate, involves inhibiting the tendency to read the words 

Wisconsin card sort test

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* **normally there is an increase in regional blood flow to the dIPFC as measured by fMRI** 

Sensory-motor gating deficits

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* difficulties screening out irrelevant stimuli and focusing on salient ones .
* when a weak stimulus precedes a startle stimulus,the normal response is to inhibit the startle, schizophrenic patients dont do this 

P50 signal in event-related potentials

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* **in  a healthy response, P50 wave o 2nd click is 80% diminished, in schizophrenic patients there is no change**

Oculomotor function

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* the eye movements of schizophrenic patients are not smooth compared to controls 

Structural (brain) difference

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* Weinberger and Wyatt 1982: the relative ventricle size of the schizophrenic patients was more than twice as big as that of normal control subjects
* Reduced brain volume in the temporal, frontal lobes and hippocampus 
* Faulty cellular arrangement in the cortex and hippocampus 

Genetics

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* Both adoption and twin studies indicate that schizophrenia is a heritable trait although it is not due to a single gene → several genes are involved 
* One rare mutation involves a gene known as DISC1 (disrupted in schizophrenia 1) → involved in the regulation of neurogenesis, neuronal migration, postsynaptic density in excitatory neurons and mitochondria function 

Paternal age

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* The children of older fathers are more likely to develop schizophrenia 
* Most likely due to mutations in the spermatocytes (cells that produce sperms)

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**Twin studies**

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* The formation of MZ (identical) twins occurs when the blastocyst splits in two
* if this happens before day 4, the two organisms develop independently
* if it happens after day 4, they share a single placenta
* The concordance rate for monochorionic MZ twins (share a placenta) was found to be 60% vs 32% in dichorionic MZ twins

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**The early neurodevelopmental model:** 

* Prenatal events cause deviations from normal neurodevelopment and these lie dormant until the brain matures sufficiently (Murray & Lewis, 1987)
* Evidence: early events such as infections, obstetric complications and nutritional deficiencies 
* Walker et al. 1994-1996 : independent observers examined the behaviour of schizophrenic children – those who subsequently became schizophrenic displayed more negative affect in their facial expressions and were more likely to do abnormal movements 

The late neurodevelopmental model

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* may result from an abnormality in adolescence when synaptic pruning takes place (Feinberg 1982)

**Two-hit model (Fatemi & Folsom, 2009; Keshavan & Hogarty, 1999)**

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* Atypical development in schizophrenia takes place during 2 critical time points: early brain development and adolescence 
* Early brain development → may lead to the dysfunction of specific neural networks that would account for premorbid signs 
* Adolescence → excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms 

The dopamine hypothesis

* Proposes the schizophrenia is caused by abnormalities in dopamine functioning in the brain
* Overactivity of dopamine in the mesolimbic system results in the positive symptoms of schizophrenia 
* Underactivity in the mesocortical system results in the negative and cognitive symptoms 

→ DA agonists induce psychosis – the symptoms that they produce can be alleviated with antipsychotic drugs 

→ chlorpromazine was developed in 1952 which had dramatic effects on schizophrenia (a DA antagonist)

Antipsychotic drugs

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* They all block D2 receptors 
* Eliminate or diminish the positive symptoms in most of the patients 
* Long-term treatment leads to some symptoms resembling those in Parkinson – ⅓ of all patients who take them for an extended period get tardive dyskinesia (unable to stop moving) 

Clozapine

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* First of the atypical antipsicotics 
* Has lower affinity for D2 and higher for other DA receptors 
* Highly effective, not widely used
* Only drug to reduce suicide rates 
* Side effects: weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia 

Problems with the dopamine hypothesis

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* Explains only positive symptoms 
* Atypical antipsychotics are better 
* Dopamine underactivity is the problem rather than dopamine overactivity

The glutamate hypothesis

* major excitatory neurotransmitter in the CNS and the most prevalent one
* glutamate is balanced with GABA
* evidence implicates NMDA receptors in schizophrenia

NMDA receptors and schizophrenia

they compromise critical components of developmental prcoesses which include:

* development of neural pathways
* neural migration
* neural survival
* neural plasticity
* neural pruning of cortical connections
* apoptosis

**Glutamate hypo-functioning hypothesis (olney and farber 1995)**

\-- schizophrenia is due to NMDA receptor hypofunctioning which may explain

* why there are so many treatment-resistant negative symptoms
* why the onset is in early adulthood
* whyt he isorder is associated with structural changes and cognitive deficits

Neuroinflammatory hypothesis

* brains immune cells are hyperactive in people who are at risk
* many animals studies show a link between pro-inflammatory agents and schizophrenia symptoms
* symptoms are reversed upon treatment with antiphsychotics or treatment with antibiotics that reduce microglial activation
* support the evidence for prenatal or preinatal infection and the increased risk for schixophrenia

Microglia

* become activated (amoeboid morphology) upon identifying a threat
* they are involved in a range of homeostatis functions in a healthy brain (e.g.: neuronal cell death, synaptogenesis, synaptic pruning)
* microgilial activation is not instantaneous in response to agents
* may lead to subtle rearrangement of synaptic circuitry -→ behavioural impairment in adolescence !!

Oestrogen hypothesis

* secreted mainly by : the ovaries, fat, breasts and the brain
* second peak onset of schizophrenia at age 45-60y (menopause)
* seems to play a protective role against the development of schizophrenia