Schizophrenia

Positive symptoms

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

• 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

→ Weinberger 1988: negative symptoms are caused by hypofrontality

Stroop task

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

Wisconsin card sort test

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

Sensory-motor gating deficits

• 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

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

Oculomotor function

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

Structural (brain) difference

• 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

• 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

• The children of older fathers are more likely to develop schizophrenia

• Most likely due to mutations in the spermatocytes (cells that produce sperms)

Twin studies

• 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

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

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

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

• 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

• 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

• 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

• 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