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Schizophrenia The term schizophrenia: term developed by eugen bleuler (1908) and refers to a break from reality. It affects 1% of the population and ancient writings of the symptoms have been around for thosands of years, the major symptoms of the disorder are universal and similar across cultures. The monetary costs exceeds the cost of all cancers and is associated with higher suicide rate (x13) compared to general population. Insel (2010) has stated that it is more of a syndrome than a disorder because It is a collection of signs and symptoms of an unknown aetiology Symptoms    

3 main catregories: positive negative and cognitive Start to emerge in early adulthood but can be earlier or later They appear gradually over 3-5 years usually Negative symptoms emerge first followed by cognitive followed by positve

Positive symptoms               

Are the well known ones commonly associated to schizophrenia Psychotic aspects of the condition: include thought disorder, delusions and hallucinations Thought disorders disorganized, irrational thinking – probably the most important symptom of schizophrenia great difficulty arranging thoughts logically, and sorting out plausible conclusions from absurd ones. during conversation they jump from one topic to another as new associations come up. - these associations may not make much sense to other people sometimes utter meaningless words or choose words for rhyme rather than for meaning. Delusions are beliefs that are contrary to fact. There are many types: persecution - false beliefs that others are plotting and conspiring against oneself. grandeur - false beliefs about one’s power and importance (godlike powers, special knowledge that no one else possesses) control - related to persecution i.e the person believes that he or she is being controlled by others through radar or a tiny radio receiver implanted in his or her brain. Hallucinations are perceptions of stimuli that are not actually present. Most common are auditory, but they can involve any of the other senses. Typically, voices talk to the person, order them to do something, scold the person for his or her unworthiness or utter meaningless phrases. Olfactory hallucinations are also fairly common and they often contribute to the delusion that others are trying to kill them

Negative symptoms     

Known by the absence or diminution of normal behaviors: flattened emotional response poverty of speech lack of initiative persistence

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anhedonia social withdrawal

Cognitive symptoms      

Cognitive symptoms are all to do with executive functions include: difficulty in sustaining attention low psychomotor speed (the ability to rapidly and fluently perform movements of the fingers, hands, and legs) deficits in learning and memory poor abstract thinking poor problem solving

These neurocognitive deficits are associated with frontal lobe hypofunction. It was suggested by Weinberger (1988) that the negative symptoms of schizophrenia are primarily caused by hypofrontality which is decreased activity in the frontal lobes – the dlPFC in particular. This leads to:       

Lower performance in IQ tests Planning and information processing deficits Attentional deficits (e.g. Stroop test) Working memory deficits (e.g. Wisconsin Card Sorting Test) Sensory-motor gating deficits (P50 and PPI tasks) Anti-saccade task Oculomotor function (eye tracking)

The stroop task RED

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BROWN

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ORANGE RED --- incongruent condition

The stroop task instruct people to try and name the colour of the ink as fast as you can (not the colour that the word says). Schizophrenia patients are slower and less accurate. Completing this task involves inhibiting our tendency to simply read the words which involves frontal lobe which why scz people find more difficult Wisconsin card sort test      

Different ways that you can sort a pack of cards (suit, colour, number) Ask participants to sort a deck of cards – not specifically how to sort them If they sort them and experimenter says not that way sort it in a different way So yoy need to think and process info which involves frontal lobes In this task scz patients do worse Also evidence of less blood flow to dlPFC in scz patients during this task measured using fMRI

Sensory – motor gating deficits   

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Sensory-motor gating deficits – difficulties screening out irrelevant stimuli and focusing on salient ones In healthy people our brains allow info to enter but we have a filter system to allow relevant info to come in and keep irrelevant info out Evidence to show that this filtering system is not functioning properly in scz – allows irrelevant info in for processing which may lead to overload

This is demonstrated through P50 signal task in ERPs (Event-Related Potentials) - make brain recordings (Freedman et al, 1987) Presented with 2 auditory stimuli (2 clicks) 500ms apart

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Healthy response - P50 wave to 2nd click is 80% diminished whereas in schizophrenic patients there is no change

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--healthy -- scz Shows how they not able to inhibit this signal so they acknowledge it as am important sources of info and allow it to enter for processing Another similar task is the pre-pulse inhibition task (PPI) When a weak stimulus precedes a startle stimulus by 100ms the normal response is to inhibit the startle but people with scz don’t do this

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Oculomotor function   

Also disturbed in people with schizophrenia In tasks where you are asked to follow a laser or something with your eyes is usually a smooth pursuit – tracking a moving stimulus Eye movements of scz patients are not so smooth and involves a lot of “catchup” saccades

 Structural differences in brain     

Evidence for differences in anatomy Weinberger and Wyatt (1982): CT scans of 80 schizophrenics and 66 healthy controls of the same mean age (29y) and measured the area of the lateral ventricles (blind study) The relative ventricle size of the schizophrenic patients was more than twice as big as that of normal control subjects – suggest neural degeneration Reduced brain volume (less grey matter) in temporal, frontal lobes and hippocampus Faulty cellular arrangement in the cortex and hippocampus

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Heritability and genetics Both adoption studies and twin studies indicate that schizophrenia is a heritable trait although it is not due to a single dominant or recessive gene. So far, no single gene has been shown to cause schizophrenia. Rather, several genes are involved. Having a “schizophrenia gene” causes a susceptibility to develop schizophrenia which may be triggered by environmental factors. Genetics     

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 Its presence appears to increase the chance of schizophrenia by a factor of 50 Also increases the incidence of other mental health conditions, including BD, and ASD (Kim et al., 2009). -- not specific to schizophrenia Genetics of scz seem to be linked to very small changes in the genetic code (snp)

Paternal age     

The effect of paternal age provides further evidence that genetic mutations may affect the incidence of schizophrenia in metanalyses by Brown et al., 2002; Sipos et al., 2004). The children of older fathers are more likely to develop schizophrenia. Most likely due to mutations in the spermatocytes, the cells that produce sperm. Following puberty, these cells divide every 16 days, which means that they have divided approximately 540 times by age 35 so there is more opportunity for mutation In contrast, a woman’s oocytes divide 23 times before birth and only once after that.

Degree of heritibility of scz doesn’t explain a larger percent of the disease population

As we look at relatives the percent of heritability goes up but in MZ twins where they share 100% of their genetic code there is only 48% change that if one twin has it the other one will – so what explains the other 52% of the variance. MZ twins there is way higher heritability than DZ twins which lead researcher to ask why this was and look at twin studies Twin studies         

MZ twins are genetically identical, but they also share the same intrauterine environment. However, the prenatal environment of monozygotic twins is not always identical The formation of MZ twins occurs when the blastocyst splits in two. If this occurs before day 4, the two organisms develop independently, each forming their own placenta – dichorionic If this occurs after day 4, the two organisms become monochorionic - share a single placenta. Studies have looked at incidence of scz between dichorionic and monochronic twins The concordance rate for monochorionic MZ twins was found to be 60% vs 32% in dichorionic MZ twins (Davis and Phelps, 1995) Issue with this study is how do you reliably tell if twins are monochoronic??? Use indicators such as fingerprints and birthmarks but you cant tell definitively So those who shared the same prenatal environment had a higher concordance Suggests something during gestation is influencing the development of the twins which explains the differing susceptibility to developing scz later in life

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Provides strong evidence for interaction between prenatal environment and herditity

Neurodevelopmental theories of SCZ  

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The ‘early’ neurodevelopmental model: Events in early life (prenatally) cause deviations from normal neurodevelopment and these lie dormant until the brain matures sufficiently to call into operation the affected systems (Murray & Lewis, 1987) Early events such as infections, obstetric complications, nutritional deficiencies etc. seem to support this theory. Evidence from pandemics e.g. influenza there was an increase in scz patients

Early evidence suggesting abnormal brain development     

Home movies from families with a schizophrenic child (Walker et al 1994,1996) Independent observers examined the behavior of the children Those who subsequently became schizophrenic displayed more negative affect in their facial expressions and were more likely to do abnormal movements. In 1972, 265 Danish children aged 11–13 years, were videotaped briefly while eating lunch (Schiffman et al. 2004) Blind raters, found that the children who later developed schizophrenia displayed less sociability and displayed deficient psychomotor functioning.

Neurodevelopmental theories      

The ‘late’ neurodevelopmental model: schizophrenia may result from an abnormality or deviation in adolescence, when synaptic pruning takes place (Feinberg, 1982/3). “Two-hit” model (Fatemi & Folsom, 2009; Keshavan and Hogarty, 1999): Atypical development in schizophrenia takes place during 2 critical time points: early brain development and adolescence. Early developmental insults may lead to dysfunction of specific neural networks that would account for premorbid signs During adolescence, excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms.

The timeline for the development of scz and the factors that play a role are a combination of genetic and environmental. We cannot inherit an “scz gene” and say with certainty that we have develop scz at some point in our lives – nevertheless it is till likely that we have genetic components that may render us susceptible but these genetic susceptibilities are difficult to identify. We can think of the genetics as the platform on which the disease may develop and this is followed by early insults such as obstetric complications, prenatal infection and nutritional deficiency which can increase chances of developing scz in early years. Finally, more adverse life events or substance abuse in adolescence may further increase chance of disease development. E.g. cannabis use increases chance of developing scz x6 Neurochemistry of schizophrenia The dopamine (DA) hypothesis

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Proposes that scz is caused by abnormalities in dopamine functioning in the brain and that overactivity of DA in the mesolimbic system results in the positive symptoms of schizophrenia Conversely, under activity of DA in the mesocortical system results in the negative and cognitive symptoms of scz For the DA hypothesis about positive symptoms: in healthy brain dopamine is produced in the VTA which is projected to the nucleus accumbens in the mesolimbic area In pathological brain there is excess production in mesolimbic system which causes positive symptoms

In healthy people they have normal levels of dopamine projected to the prefrontal cortex so they have normal functioning in psychological tests. In scz patients too little dopamine in this area leads to negative and cognitive symptoms

Evidence for the DA hypothesis     

DA agonists produce symptoms that resemble the positive symptoms of schizophrenia. These drugs include amphetamine, cocaine, methylphenidate (Ritalin) and L-DOPA (parkinsons treatment) The symptoms that they produce can be alleviated with antipsychotic drug strengthens the argument that the antipsychotic drugs exert their therapeutic effects by blocking DA receptors. Chlorpromazine: first antipsychotic developed had dramatic effects on schizophrenia and was a dopamine antagonist

Antipsychotic drugs    

Since the discovery of CPZ, many drugs have been developed for the treatment of schizophrenia – typical antipsychotics Two major families of DA receptors: D1-type family (Gs coupled): D1 & D5 type receptors D2-type family (Gi coupled): D2, D3, D4

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These drugs have one property in common: They block D2 receptors There is a strong correlation with effectiveness of antipsychotic and its affinity to D2 receptor

Studies using a radiotracer (can be tracked) called Idobenzamine which is a D2 receptor reversible ligand which means that it will compete with DA to bind to its receptors But is there is dopamine around it will be displaced so dopamine can bind to the receptor (reversible) Study by Dargham (1998) have shown that in scz population there is more dopamine being released compared to controls because if we give IBZM then induce dopamine release by giving amphetamines we see more displacement of IBZM in scz compared to control which indicates that there may be to much dopamine in scz

Treatment with typical antipsychotics issues    

These drugs eliminate, or at least diminish the positive symptoms in most of the patients. About 20-30% do not respond to these drugs Do not tackle negative or cognitive symptoms Long-term treatment leads to at least some symptoms resembling those in Parkinson’s disease: slowness in movement, lack of facial expression, and general weakness. A more serious side effect develops in ~1/3 of all patients who took the drugs for an extended period: tardive dyskinesia - patients with tardive dyskinesia are unable to stop moving.

Atypical antipsychotics   

Atypical antipsychotics work in treatment-resistant patients Atypicals do not have the Parkinsonian side-effects due to the fact that they have lower affinity for the D2 receptors Also affect other neurotransmitter systems such as serotonin, acetylcholine

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Improve both positive and negative symptoms of schizophrenia Also improve the performance in neuropsychological tests which is not the case with typical antipsychotics e.g. Clozapine Clozapine, the first of the atypical antipsychotic drugs (followed by others: risperidone, olanzapine, ziprasidone, and aripiprazole) Has lower affinity for D2 and higher affinity for other DA receptors (D3, D4 and even 5HT) Although it is highly effective it is still not widely used – despite international consensus to use it when other drugs have failed The only antipsychotic to reduce suicide rates in schizophrenics Still considered to be tricky due to its side effects: weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia etc.

Problems with dopamine hypothesis: it explains only a part of schizophrenia (positive symptoms not negative symptoms). Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better antipsychotics. Negative symptoms are caused by under-activity in the mesocortical dopamine pathway. So, dopamine underactivity is the problem rather than dopamine overactivity – jow can this imbalance be caused in scz patients? Glutamate hypothesis           

Glutamate is the major excitatory neurotransmitter in the central nervous system and the most prevalent one (the king of neurotransmission) Nearly 50% of the neurons in the brain, including all neurons that project from the cerebral cortex, are believed to use glutamate as their neurotransmitter. In mammalian brains, glutamate is balanced with GABA (main inhibitory chemical transmitter) Both neurotransmitters influence almost every other chemical and brain area. Evidence implicates NMDA receptors in schizophrenia NMDA receptor is an ionotropic receptor (tetramer NR1 & NR2) At rest the channel is blocked by Mg2+ When open it allows for Ca2+ influx Activation of NMDA can support learning and memory (LTP, spine proliferation and trophic effects) but too much can be excitotoxic. NMDA receptors comprise a critical component of developmental processes which include: o o o o o o

Development of neural pathways Neural migration Neural survival Neural plasticity Neural pruning of cortical connections Apoptosis

Olney & Farber (1995) came up with the glutamate hypo-functioning hypothesis – suggests that scz is due to NMDA hypofunction which may explain:   

There are so many treatment resistant negative symptoms Why the onset is early adulthood Why the disorder is associated with structural changes and cognitive deficits

Evidence 

The drugs Phencyclidine (PCP, also known as “angel dust”) and ketamine (“Special K”), can cause positive, negative, and cognitive symptoms of schizophrenia

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Both of them are NMDA receptor antagonists Glutamate agonists seem to improve both positive and negative symptoms of schizophrenia Evidence in support from animal genetic studies with NMDA receptor subunits as well as GWAS The negative and cognitive symptoms produced by ketamine and PCP are caused by a decrease in the metabolic activity of the frontal lobes. Jentsch et al. (1997) administered PCP to monkeys twice a day for two weeks. - A week later, tested the animals on a task that involved reaching around a barrier for a piece of food - Performance depends on the function of the PFC (animals with lesions of the PFC perform poorly). - Control monkeys performed well, but those treated with PCP showed a severe deficit.

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Glutamate hypothesis: positive symptoms   

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Implicates a hypofunctional NMDA receptor in the prefrontal cortex located on the GABAergic interneurons in the frontal cortex Argues glutamate neuron in the prefrontal cortex is synapsing onto and stimulating GABAergic interneurons In healthy brain these GABAergic interneurons will inhibit a glutamatergic pathway which will come down to the VTA which allows for normal level of dopamine release in mesolimbic pathway In pathological brain the glutamate NMDA receptor which synapses onto and stimulates the GABAergic interneuron in prefrontal...