Schizophrenia

Question 1

Schizophrenia:

Answer 1

· Eugen Bleuler (1908) – term “schizophrenia” to refer to a break from reality
· Afflicts 1% of the world’s population
· Ancient writings indicate that the disorder has been around for thousands of years
· The major symptoms of schizophrenia are universal, similar across cultures
· Monetary cost - exceeds the cost of all cancers and is associated with much higher (13x) suicide rate compared to the general population
· Schizophrenia is a syndrome – ‘a collection of signs and symptoms of unknown aetiology’ (Insel, 2010, Nature)

Question 2

Symptoms of schizophrenia:

Answer 2

· Three categories of symptoms: positive, negative, and cognitive
· Symptom onset is usually in early adulthood but can happen earlier or later
· Appear gradually, over a period of 3-5 years.
- Negative symptoms are the first to emerge, followed by cognitive symptoms. The positive symptoms emerge last

Question 3

Positive symptoms:

Answer 3

· Make themselves known by their presence (excess)
· They include thought disorders, delusions and hallucinations

Question 4

Positive symptoms - thought disorders:

Answer 4

· 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.
· sometimes utter meaningless words or choose words for rhyme rather than for meaning.

Question 5

Positive symptoms - delusions:

Answer 5

· 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.

Question 6

Positive symptoms - hallucinations:

Answer 6

· 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

Question 7

Negative symptoms:

Answer 7

· Known by the absence or diminution of normal behaviors:
- flattened emotional response
- poverty of speech
- lack of initiative
- persistence
- anhedonia
- social withdrawal

Question 8

Cognitive symptoms:

Answer 8

· 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

Question 9

Cognitive symptoms 2:

Answer 9

· All neurocognitive deficits are associated with frontal lobe hypofunction
· Weinberger (1988) suggested that the negative symptoms of schizophrenia are caused primarily by hypofrontality, decreased activity of the frontal lobes, the dlPFC in particular
- 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

Question 10

The stroop task:

Answer 10

· The instructions are to name the colour of the ink in two conditions: congruent and incongruent
· Schizophrenia patients are slower and less accurate
· Involves inhibiting the tendency to read the word

Question 11

Wisconsin card sort test:

Answer 11

· Normally, during the task, there is an increase in regional blood flow to the diPFC as measured by fMRI

Question 12

Sensory-motor gating deficits:

Answer 12

· Sensory-motor gating deficits – difficulties screening out irrelevant stimuli and focusing on salient ones
· P50 signal in ERPs (Event-Related Potentials)
- Presented with 2 auditory stimuli (2 clicks) 500ms apart
- Healthy response - P50 wave to 2nd click is 80% diminished whereas in schizophrenic patients there is no change

Question 13

Sensory-motor gating deficits - pre-pulse inhibition (PPI):

Answer 13

· When a weak stimulus precedes a startle stimulus by ~100ms the normal response is to inhibit the startle
· People with schizophrenia do not inhibit the startle

Question 14

Oculomotor function:

Answer 14

· Smooth pursuit - Tracking a moving stimulus
· The eye movements of schizophrenic patients are not smooth compared to controls (“catchup” saccades)

Question 15

Structural differences:

Answer 15

· 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
· Reduced brain volume (less grey matter) in temporal, frontal lobes and hippocampus
· Faulty cellular arrangement in the cortex and hippocampus

Question 16

Heritability and genetics:

Answer 16

· 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.

Question 17

Genetics of schizophrenia:

Answer 17

· 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).

Question 18

Paternal age:

Answer 18

· The effect of paternal age provides further evidence that genetic mutations may affect the incidence of schizophrenia (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
- In contrast, a woman’s oocytes divide 23 times before birth and only once after that.

Question 19

Neurodevelopmental theories - the ‘early’ neurodevelopmental model:

Answer 19

· 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. provide evidence in support of this theory.

Question 20

Early evidence suggesting deviations in brain and development:

Answer 20

· 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.

Question 21

Neurodevelopmental theories - the ‘late’ neurodevelopmental model:

Answer 21

· schizophrenia may result from an abnormality or deviation in adolescence, when synaptic pruning takes place (Feinberg, 1982/3).

Question 22

Neurodevelopmental theories - “Two-hit” model (Fatemi & Folsom, 2009; Keshavan and Hogarty, 1999):

Answer 22

· 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

Question 23

The dopamine (DA) hypothesis:

Answer 23

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

Question 24

DA agonists induce psychosis:

Answer 24

· DA agonists produce symptoms that resemble the positive symptoms of schizophrenia.
· These drugs include amphetamine, cocaine, methylphenidate and L- DOPA.
· The symptoms that they produce can be alleviated with antipsychotic drugs
- strengthens the argument that the antipsychotic drugs exert their therapeutic effects by blocking DA receptors.

Question 25

DA antagonists:

Answer 25

· Henri Laborit (mid 20thce): French surgeon who discovered that a drug used to prevent surgical shock also reduced anxiety.
· A related compound called chlorpromazine (CPZ) was developed in 1952 which had dramatic effects on schizophrenia.
· CPZ is a DA antagonist – first antipsychotic

Question 26

Antipsychotic drugs:

Answer 26

· 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
- D2-type family (Gi coupled): D2, D3, D4
· These drugs have one property in common: They block D2 receptors

Question 27

More evidence in support of DA’s involvement:

Answer 27

· SPECT study using Iodobenzamine (IBZM), as a radiotracer.
· IBZM is a D2 receptor reversible ligand which means that it will compete with DA for binding to that receptor
· Measured displacement after treatment with amphetamine in striatum (Abi-Dargham 1998, Am J. Psychiatry, 155, 761-70)
· More displacement of IBZM means more DA activity
· More DA activity in striatum correlated with positive symptoms

Question 28

Treatment with typical antipsychotics:

Answer 28

· These drugs eliminate, or at least diminish the positive symptoms in most of the patients. About 20-30% do not respond to these drugs
· 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

Question 29

Newer drugs - atypical antipsychotics:

Answer 29

· 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
· Improve both positive and negative symptoms of schizophrenia
- Also improve the performance in neuropsychological tests which is not the case with typical antipsychotics

Question 30

Clozapine:

Answer 30

· 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

Question 31

Problems with the dopamine hypothesis:

Answer 31

· 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

Question 32

The glutamate system:

Answer 32

· Glutamate is the major excitatory neurotransmitter in the central nervous system and the most prevalent one (the king of neurotransmission)
· Many neurons in the brain, including all neurons that project from the cerebral cortex, 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

Question 33

NMDA receptor:

Answer 33

· 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

Question 34

NMDA and schizophrenia:

Answer 34

· NMDA receptors comprise a critical component of developmental processes which include:
- Development of neural pathways
- Neural migration
- Neural survival
- Neural plasticity
- Neural pruning of cortical connections
- Apoptosis

Question 35

Glutamate hypo-functioning hypothesis:

Answer 35

· Schizophrenia is due to NMDA receptor hypofunction which may explain:
a. Why there are so many treatment-resistant negative symptoms
b. Why the onset is in early adulthood
c. Why the disorder is associated with structural changes and cognitive deficits

Question 36

Glutamate hypofunctioning hypothesis 2:

Answer 36

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

Question 37

Positive and negative symptoms - role of the PFC:

Answer 37

· 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.

Question 38

Hypo-functioning NMDA receptors theory:

Answer 38

· This theory is more comprehensive - it can explain the positive, negative & cognitive symptoms of schizophrenia
· It accounts for the lack of effectiveness of DA antagonists in treating schizophrenia
· Hypo-functioning NMDA receptors can account for both the excessive DA release in the mesolimbic DA system as well as the reduced release of DA in the prefrontal cortex

Question 39

Microglial activation and schizophrenia:

Answer 39

· The brain’s immune cells are hyperactive in people who are at risk of developing schizophrenia
· Many animals studies show a link between pro-inflammatory agents and schizophrenia symptoms
· The symptoms are reversed upon treatment with antipsychotics or treatment with antibiotics that reduce microglial activation
· Support the evidence for prenatal or perinatal infection and the increased risk for schizophrenia

Question 40

PET imaging in healthy volunteers, high-risk subjects and patients with schizophrenia:

Answer 40

Stepwise elevation in microglial activity (in orange) as the severity of the illness increases

Question 41

Recent genome-wide association studies of schizophrenia:

Answer 41

· Identified 100+ genetic loci that contribute to schizophrenia risk.
· The dopamine-receptor gene, DRD2, GLU receptor subunits etc are associated with risk of schizophrenia.
· Most significant association is on chromosome 6 which includes a region of genes involved in acquired immunity (major histocompatibility complex - MHC).

Question 42

Microglia:

Answer 42

· In healthy conditions they are in a ramified state and survey the brain for pathogens or debris
· Upon identification of a threat they become activated (amoeboid morphology)
· Their function goes beyond the immune system – involved in a range of homeostatic functions in a healthy brain such as:
- Neuronal cell death and survival
- Synaptogenesis
- Synaptic pruning etc

Question 43

Microglial activation and schizophrenia in animal studies:

Answer 43

· Interestingly, microglial activation is not instantaneous in response to infectious agents
- grows steadily throughout the lifespan, reaching a peak in late adolescence and early adulthood
· Thus, a pre- or perinatal infection primes microglia and this priming may interact with cells in the developing nervous system
· May lead to a subtle rearrangement of synaptic circuitry resulting in behavioral impairment in adolescence

Question 44

Oestrogen (estrogen) hypothesis of schizophrenia:

Answer 44

· Estrogen is the primary “female” sex hormone with 17β-estradiol being the most potent form
· 17β-estradiol is secreted mainly by the ovaries, fat, breasts and the brain (neuroprotective effect)
· In women there is a 2nd peak onset of schizophrenia at age 45-50y (menopause)
· Estrogen seems to play a protective role against the development of schizophrenia (buffer)

Question 45

Estrogen hypothesis of schizophrenia:

Answer 45

· Women seem to have:
- Less severe course, less severe negative symptoms
- Later onset which is linked to better prognosis
- Better response to antipsychotic treatment, fewer hospitalizations and less disability (self-care, remain employed, more likely to be married, keep family and friends)
- Support the hypothesis that sex hormones may also play a role in the aetiology and treatment of schizophrenia