10. Schizophrenia Flashcards
Eugen Bleuler (1908) - term ‘schizophrenia’ to refer to a b____ from r____
break from reality
Schizophrenia affects __% of the world’s population
1%
The major symptoms of schizophrenia are u____, meaning they are s____ across c____
universal, similar, cultures
Schizophrenia has a m____ cost but is also associated with very high (__x) s____ rate compared to the general population
monetary
14x suicide
Schizophrenia is a s____ - ‘a collection of s____ and s____ of u____ aetiology’
syndrome, signs, symptoms, unknown
There are three categories of symptoms of SZ:
1. N____
2. C____
3. P____
- Negative
- Cognitive
- Positive
Symptom onset is usually in e____ a____ but can happen earlier or later
early adulthood
Symptoms appear g____, over a period of __-__ years
gradually, 3-5
N____ symptoms are first to emerge, followed by c____ symptoms. The p____ symptoms emerge last
negative, cognitive, positive
Positive symptoms make themselves known by their p____ (e____). They include t____ disorders, d____ and h____.
presence (excess)
thought, delusions, hallucinations
Thought disorders:
1. D____, i____ thinking - probably the most i____ symptom of SZ
2. Great difficulty a____ thoughts l____, and sorting out p____ conclusions from a____ ones
3. During conversation they j____ from one topic to another as new a____ come up
4. Sometimes utter m____ words or choose words for r____ rather than for m____
- Disorganised, irrational, important
- arranging, logically, plausible, absurd
- jump, associations
- meaningless, rhyme, meaning
Delusions are a positive symptom. They are beliefs that are c____ to f____. There are many types including:
1. P____ - false belief that others are p____ and c____ against oneself
2. G____ - false beliefs about one’s p____ and i____
3. C____ - related to p____
contrary, fact
1. Persecution, plotting, conspiring
2. Grandeur, power, importance (godlike powers, special knowledge that no one else possesses)
3. Control, 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 a type of positive symptom. They are p____ of s____ that are not actually p____. They are most commonly a____, but can involve any of the other senses. Typically v____ talk to the person, o____ them to do something, s____ the person for their unworthiness or utter m____ phrases. O____ hallucinations are also common and contribute to the delusion that others are trying to k____ them.
perceptions, stimuli, present
auditory
voices, order, scold, meaningless
Olfactory, kill
Negative symptoms are known by the a____ or d____ of normal behaviours. They include:
1. F____ e____ response
2. P____ of speech
3. Lack of i____
4. P____
5. A____
5. S____ w____
absence, diminution
1. flattened emotional
2. poverty
3. initiative
4. persistence
5. anhedonia
5. social withdrawal
Cognitive symptoms include:
1. Difficulty in s____ a____
2. Low p____ speed
3. Deficits in l____ and m____
4. Poor a____ thinking
5. Poor p____ s____
- sustaining attention
- psychomotor (the ability to rapidly and fluently perform movements of the fingers, hands, and legs)
- learning, memory
- abstract
- problem solving
All neurocognitive deficits are associated with f____ l____ h____. Weinberger (1988) suggested that the negative symptoms of schizophrenia are caused primarily by h____ (decreased activity of the f____ l____), the dlPFC in particular
frontal lobe hypofunction, hypofrontality, frontal lobes
In the stroop task, people with schizophrenia are s____ and less a____
slower, accurate
Normally, during the Wisconsin Card Sort Test, there is an increase in r____ b____ flow to the dlPFC as measured by fMRI.
regional blood
People with SCZ show s____-m____ g____ deficits. This means difficulties screening out i____ stimuli and focusing on s____ ones
sensory-motor gating
irrelevant, salient
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
Pre-pulse inhibition:
When a weak stimulus precedes a s____ stimulus by ~100ms the normal response is to i____ the s____. People with schizophrenia do not i____ the s____.
startle, inhibit, startle, inhibit, startle
Smooth pursuit is tracking a m____ stimulus and measures o____ function. The eye movements of schizophrenic patients are not s____ compared to controls (‘c____’ saccades)
moving, oculomotor
smooth, catchup
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 t____ a____ b____ as that of normal control subjects. There was reduced brain volume (less grey matter) in t____, f____ lobes and h____. Faulty cellular arrangement in the c____ and h____.
twice as big
temporal, frontal, hippocampus
cortex, hippocampus
Both adoption studies and twin studies indicate that schizophrenia is a h____ trait although it is not due to a single d____ or r____ gene. Having a “schizophrenia gene” causes a s____ to develop SCZ which may be t____ by e____ factors
heritable, dominant, recessive
susceptibility, triggered, environmental
One rare mutation involves a gene known as DISC1 (d____ i____ s____ 1). It involves the regulation of n____, neuronal m____, postsynaptic d____ in e____ neurons and m____ function.
disrupted in schizophrenia
neurogenesis, migration, density, excitatory, mitochondria
It was initially thought that DISC1 increased the chance of SCZ by a factor of __.
Also increases the incidence of other MHC, such as B____ and A____.
Mathieson, Munafo & Flint (2011) – Meta-analysis concluded that DISC1 is n____ a____ with schizophrenia
50
BD, ASD
not associated
The effect of p____ a____ provides further evidence that genetic mutations may affect the incidence of schizophrenia. The children of o____ f____ are more likely to develop SCZ. Most likely due to the mutations in the s____ (the cells that produce s____)
paternal age
older fathers
spermatocytes, sperm
MZ twins are genetically identical, but they also share the same i____ environment. However, the p____ environment of monozygotic twins is not always identical.
The formation of MZ twins occurs when the b____ splits in two.
If this occurs before day __, the two organisms develop independently, each forming their own placenta – d____
If this occurs after day __, the two organisms become m____ - share a single placenta.
The concordance rate for monochorionic MZ twins was found to be __% vs __% in dichorionic MZ twins (Davis and Phelps, 1995)
intrauterine, prenatal
blastocyst, 4, dichorionic
4, monochorionic
60% vs 32%
One neurodevelopment theory of SCZ is the ‘e____’ neurodevelopment model:
1. Events in e____ life (p____) cause deviations from normal neurodevelopment and these lie d____ until the brain matures sufficiently to call into operation the a____ systems
2. E____ events such as i____, obstetric complications, n____ deficiencies etc provide evidence in support of this theory
early
1. early, prenatal, dormant, affected
2. early, infections, nutritional
Early evidence suggesting deviations in brain development:
1. 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 n____ a____ in their f____ e____ and were more likely to do a____ m____.
2. 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 s____ and displayed d____ p____ f____.
- negative affect, facial expressions, abnormal movements
- sociability, deficient psychomotor functioning
One neurodevelopment theory of SCZ is the “l____” neurodevelopment model which states that SCZ may result from an a____ or d____ in a____, which s____ p____ takes place
late, abnormality, deviation, adolescence, synaptic pruning
One neurodevelopment theory of SCZ is the “T____-h____” model that states atypical development in SCZ takes place during 2 critical time points:
1. E____ b____ development
2. A____
Early developmental insults may lead to dysfunction of specific n____ n____ that would account for p____ signs
During adolescence, excessive s____ p____ and loss of p____ may account for the emergence of symptoms.
Two-hit
1. early brain
2. adolescence
neural networks, premorbid
synaptic pruning, plasticity
The Dopamine (DA) Hypothesis proposes that SCZ is caused by abnormalities in dopamine functioning in the brain. O____ of DA in the m____ system results in p____ symptoms of SCZ. U____ od DA in the m____ system results in n____ and c____ symptoms of SCZ
overactivity, mesolimbic, positive
under activity, mesocortical, negative, cognitive
DA a____ induce psychosis:
1. DA a____ produce symptoms that resemble the p____ symptoms of schizophrenia.
2. These drugs include a____, c____, methylphenidate and L____
3. The symptoms that they produce can be alleviated with a____ drugs which strengthens the argument that the a____ drugs exert their therapeutic effects by blocking DA r____.
agonists
1. agonists, positive
2. amphetaminem, cocaine, L-DOPA
3. antipsychotic, antipsychotic, receptors
Henri Laborit (mid 20thce) was a French surgeon who discovered that a drug used to prevent surgical shock also r____ a____. A related compound called c____ (CPZ) was developed in 1952 which had dramatic effects on schizophrenia. CPZ is a DA a____… the first a____.
reduced anxiety
chlorpromazine
antagonist, antipsychotic
There are two major families of DA receptors:
1. D1-type family (Gs coupled): D1 & D5
2. D2-type family (Gi coupled): D2, D3, D4
T____ antipsychotics all block D__ receptors
typical, D2
Evidence in support of DA’s involvement:
SPECT study using Iodobenzamine (IBZM), as a radiotracer.
IBZM is a D__ receptor reversible ligand which means that it will c____ with DA for binding to that receptor
Measured d____ after treatment with amphetamine in s____.
More d____ of IBZM means more DA activity
More DA activity in s____ correlated with p____ symptoms
D2, compete
displacement, striatum
displacement
striatum, positive
Treatment with Typical Antipsychotics:
1. These drugs e____ (or at least d____) the p____ symptoms in most of the patients. About __-__% do not respond to these drugs
2. Long-term treatment leads to at least some symptoms resembling those in P____ d____: slowness in movement, lack of facial expression and general weakness
3. A more serious side effect develops in ~1/3 of all patients who took the drugs for an extended period: t____ d____ - patients with TD are unable to s____ m____
- eliminate, diminish, positive, 20-30%
- Parkinson’s disease
- tardive dyskinesia, stop moving
Atypical Antipsychotics:
1. Atypical Antipsychotics work in t____-r____ patients
2. They do not have the P____ side-effects do to the fact they have l____ a____ for the D2 receptors
3. They improve both p____ and n____ symptoms of SCZ
4. Also improve the performance in n____ tests which us not the case for typical antipsychotics
- treatment-resistant
- Parkinsonian, lower affinity
- positive, negative
- neuropsychological
Clozapine was the first of the a____ antipsychotic drugs.
Has lower a____ for D__ and higher affinity for other DA receptors (D3, D4 and even 5HT).
Although it is highly e____ it is still not widely used.
The only antipsychotic to reduce s____ r____ in schizophrenics
Still considered to be tricky due to its side effects: w____ g____, s____, h____, tachycardia, h____, neutropenia etc.
atypical
affinity, D2
effective
suicide rates
weight gain, sedation, hypersalivation, hypotension
Problems with the dopamine hypothesis:
1. It explains only a p____ of SCZ
2. A____ antipsychotic drugs with weaker a____-d____ activity are better antipsychotics
3. Negative symptoms are cause by u____ in the m____ dopamine pathway so dopamine u____ is the problem rather than dopamine o____
- 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 inthe mesocortical dopamine pathway
So, dopamine underactivity is the problem rather than dopamine overactivity
The Glutamate System:
1. Glutamate is the major e____ n____ 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 c____ c____, use glutamate as their neurotransmitter.
- In mammalian brains, glutamate is balanced with G____ (main inhibitory chemical transmitter)
- Both neurotransmitters influence almost every other c____ and b____ a____.
- Evidence implicates N____ r____ in schizophrenia
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
NMDA receptor:
1. NMDA receptor is an i____ receptor (tetramer NR1 & NR2)
- At rest the channel is blocked by M____
- When open it allows for C____ i____
- Activation of NMDA can support l____ and m____ (LTP, spine proliferation and trophic effects) but too much can be e____
- 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:
1. Development of n____ pathways
2. Neural m____
3. Neural s____
4. Neural p____
5. Neuronal p____ of c____ connections
6. A____
Development of neural pathways
Neural migration
Neural survival
Neural plasticity
Neural pruning of cortical connections
Apoptosis
Glutamate Hypo-functioning Hypothesis(Olney and Farber, 1995):
SCZ is due to N____ r____ hypo function which may explain why:
1. Why there are so many t____-r____ negative symptoms
- Why the onset is in e____ a____
- Why the disorder is associated with s____ c____ and c____ d____.
Why there are so many treatment-resistant negative symptoms
Why the onset is in early adulthood
Why the disorder is associated with structural changes and cognitive deficits.
Evidence supporting the Glutamate Hypofunctioning Hypothesis:
1. The drugs Phencyclidine (PCP, also known as “angel dust”) and k____ (“Special K”), can cause positive, negative, and cognitive symptoms of schizophrenia
…Both of them are NMDA receptor a____
- Glutamate a____ seem to improve both p____ and n____ symptoms of schizophrenia
- Evidence in support from a____ g____ studies with NMDA receptor subunits as well as GWAS
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
The negative and cognitive symptoms produced by ketamine and PCP are caused by a decrease in the m____ a____ of the f____ l____.
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.
Hypo-functioning NMDA Receptors Theory:
1. This theory is more c____ - it can explain the positive, negative & cognitive symptoms of schizophrenia
- It accounts for the lack of e____ of DA a____ in treating schizophrenia
- Hypo-functioning NMDA receptors can account for both the e____ DA release in the m____ DA system as well as the r____ release of DA in the p____ c____
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
Microglial activation and schizophrenia:
1. The brain’s i____ cells are h____ in people who are at risk of developing schizophrenia
- Many animals studies show a link between p____-i____ a____ and schizophrenia symptoms
- The symptoms are r____ upon treatment with antipsychotics or treatment with a____ that reduce microglial activation
- Support the evidence for p____ or p____ infection and the increased risk for schizophrenia
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
When looking at PET imaging in healthy volunteers, high-risk subjects and patients with schizophrenia, there is a s____ e____ in microglial activity (in orange) as the severity of the illness increases.
stepwise elevation
Recent Genome-Wide Association Studies of schizophrenia have identified __+ genetic loci that contribute to SCZ risk.
The d____-r____ gene, DRD2, GLU receptor subunits etc are associated with risk of schizophrenia.
Most significant association is on chromosome __ which includes a region of genes involved in a____ i____ (major histocompatibility complex - MHC).
100+
dopamine-receptor
6, acquired immunity
Microglia:
1. In healthy conditions they are in a ramified state and s____ the brain for p____ or d____
- Upon identification of a t____ they become activated (amoeboid morphology)
- Their function goes beyond the immune system – involved in a range of h____ functions in a healthy brain such as:
a) Neuronal cell d____ and s____
b) S____
c) Synaptic p____ etc
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
Microglial activation and schizophrenia in animal studies:
1. Microglial activation is not i____ in response to i____ agents. It grows steadily throughout the l____, reaching a peak in late a____ and early a____
- Thus, a pre- or perinatal infection p____ microglia and this p____ may interact with cells in the developing nervous system
- May lead to a subtle r____ of synaptic circuitry resulting in b____ i____ in adolescence
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
Oestrogen (estrogen) Hypothesis of Schizophrenia:
1. Estrogen is the primary “f____” sex hormone with 17β-estradiol being the most potent form
- 17β-estradiol is secreted mainly by the o____, f____, b____ and the b____ (neuroprotective effect)
- In women there is a 2nd peak onset of schizophrenia at age __-__y (menopause)
- Estrogen seems to play a p____ role against the development of schizophrenia (b____)
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)
Estrogen Hypothesis of Schizophrenia…
Women seem to have:
1. Less severe c____, less severe n____ symptoms
- L____ o____ which is linked to better prognosis
- Better response to a____ treatment, fewer h____ and less d____ (self-care, remain employed, more likely to be married, keep family and friends)
- Support the hypothesis that s____ h____ may also play a role in the aetiology and treatment of schizophrenia
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
