Lectures 6-8 (schizophrenia) Flashcards
(176 cards)
1
Q
the lifetime prevalence of schizophrenia is ___%
the annual incidence rates of schizophrenia is from _____ per 1000 population
A
1%; 0.1-0.4
2
Q
who are the founding fathers of schizophrenia?
A
emil kraepelin, eugen bleuler
3
Q
what did Kraeplin describe?
A
described a syndrome called “Dementia Praecox”, characterized by an early onset and progressive deterioration in intellectual functioning.
4
Q
who coined the term schizophrenia and what does it mean?
A
bleuler; splitting of mind
5
Q
Bleuler’s term schizophrenia does not mean two separate minds. what does it mean ?
A
a fragmentation of cognitive associations
6
Q
what did both kraepelin and bleuler emphasize about schizophrenia?
A
Both emphasized schizophrenia to be a disease with varied symptoms at the clinical level, but at a more fundamental level, a disease with an abnormality of the fundamental cognitive process of thinking.
Kraepelin and Bleuler both considered the disorder to be a brain disease
7
Q
(T/F): Signs and symptoms of schizophrenia encompass the entire range of human mental activity.
A
true
8
Q
what abnormalities do we see in schizophrenia (6)?
A
perception, emotion, inferential thinking, language, behavioral control and social interaction
9
Q
what dsm5 category is schizophrenia in and how is the category defined?
A
“Schizophrenia Spectrum and Other Psychotic Disorders”
defined by abnormalities in one or more of the following five domains: delusions, hallucinations, disorganized thinking (speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms.
10
Q
what are other disorders in the schizophrenia spectrum category?
A
Schizotypal personality disorder,
Delusional disorder,
Schizophreniform disorder,
Schizoaffective disorder,
Substance/medication-induced psychotic disorder,
Psychotic disorder due to another medical condition.
11
Q
how do the other disorders in the schizophrenia spectrum category differ from schizophrenia?
A
These other disorders differ from schizophrenia in number of symptoms, duration of illness and presence/absence of mood disorders.
12
Q
Diagnosis is purely ____ and ____ based - on the basis of a set of presenting ___ and _____.
A
Diagnosis is purely clinical and criterion based - on the basis of a set of presenting signs and symptoms.
13
Q
(T/F): the diagnostic criteria of schizophrenia has low reliability and great validity
A
false:
- good reliability
- validity unresolved due to absence of biological markers
14
Q
why can we say that schizophrenia is a heterogeneous disorder?
A
variability in symptoms, response to treatment, and functional impact.
Some people have argued that this heterogeneity may reflect multiple diseases within a clinical syndrome rather than individual variations of a single disease process.
15
Q
what are the two categories of symptoms in schizophrenia included in dsm5?
A
positive and negative
16
Q
what third category of symptoms is an integral part of schizophrenia phenotype but is not included in the dsm5?
A
cognitive symptoms
17
Q
what are positive symptoms? (5)
A
- Hallucinations - perception of non-existent stimuli (auditory, visual, somatic or olfactory).
- Delusions - made of unfounded, unrealistic, idiosyncratic beliefs, including delusions of: persecution, grandiosity, being controlled, mind reading, thought broadcasting.
- Bizarre behavior - inappropriate dress, inappropriate sexual and/or social behavior, aggression, agitation.
- Hostility - sarcasm, abuse and assaultiveness, uncooperativeness.
- Conceptual Disorganization or positive formal thought disorders - incoherence of thought and speech, difficulty in organizing thoughts, illogicality.
18
Q
what are the negative symptoms? (5)
A
- Affective flattening marked by diminished emotional responsiveness, including: few expressive gestures, changes in facial expression or stilted, forced or artificial gestures, poor eye contact, lack of vocal inflexion, decreased spontaneous movements.
- Alogia - includes poverty of speech and of its content. Lack of spontaneity and flow of conversation, lack of ability to communicate.
- Avolition, apathy, associated with social withdrawal: physical anergia, impaired grooming and hygiene, lack of persistence in performing activities.
- Anhedonia, asociality - few recreational interests/activities, personal and sexual relationship is impaired, uncommunicative and detached, distant.
- Attention is marked by impaired concentration: social inattentiveness, inattentiveness during conversation/interview, poor rapport.
19
Q
what are the gender differences in schizophrenia?
A
generally observed that men with schizophrenia have worse premorbid functioning, more negative symptoms particularly social withdrawal, and greater substance abuse compared to women patients.
Women with schizophrenia, on the other hand, often present with more mood disturbance and affective symptoms than men.
20
Q
what is the course of schizophrenia? (3)
A
Typically, the clinical symptoms first appear in late adolescence around ages 15-19.
The incidence rate rises sharply between 20-25 years which can be called the peak age of onset (for both genders).
The incidence then declines around 40 years; however, a small number of individuals can still be affected by schizophrenia even after 40-45 years of age (the “late onset schizophrenia”, with predominantly positive symptoms).
21
Q
what is the risk ratio for schizophrenia in genders?
A
1.4:1 for m:f
22
Q
why do women show a higher mean age of onset than men (by about 3-4 years) and comprise a larger proportion of late-onset schizophrenia cases?
A
the rate of incidence of schizophrenia in women, after the peak age of onset, shows slower age-dependent decline compared to men.
22
Q
A
23
Q
what is childhood-onset schizophrenia ?
A
A rare form of very early onset of schizophrenia with poor prognosis
24
what are the two behavioural antecedents of schizophrenia?
these are present before full blown psychotic symptoms and medical attention
premorbid phase; and prodromal phase
25
what is the premorbid phase?
characterized by subtle and nonspecific cognitive, motor and/or social dysfunction
26
what is the prodromal phase?
characterized by attenuated positive symptoms or declining function
27
which phase is more important to prevent schizophrenia?
prodromal phase
28
what are the four different outcomes after the onset of psychotic phase?
1. most patients go through functional deterioration for the next 5-10 years.
2. About 10% commit suicide.
3. Most patients stabilize, albeit at a lower level of functioning, with medications.
4. The rest are in and out of hospitals intermittently.
29
Symptoms are nearly completely controlled in about ___% of cases. Another ___% are refractory to treatments and require continuous hospitalization.
20;20
30
what is the ethology of schizophrenia?
unknown, but appears to involve an interplay between genetic and environmental risk factors.
31
what are the environmental risk factors (6)?
- people born to mothers with viral/bacterial infections during mid-late pregnancy are at 2-fold risk
- obstetric and birth complications (increase 2-fold)
- perinatal injury (neonatal seizures, asphyxia, intraventricular hemorrhage) increases by 7-fold
- patients with temporal lobe epilepsy (2 fold increase and 3x increase to develop schizophrenia-like psychosis)
- being in urban centres and migrant populations
- cannabis use in adolescence (2x)
32
____ (MIA) is posited to be a significant risk factor for schizophrenia as well as for other neurodevelopmental disorders such as autism.
Maternal immune activation
33
what is the debate about cannabis use and schizophrenia? (3)
Causality, i.e., cannabis causing schizophrenia, is implied by the observation that the risk increases in proportion to the amount of the drug used.
it is also suggested that a common genetic risk may underlie both cannabis use and schizophrenia.
there is also the suggestion of “reverse causality”, i.e., schizophrenia and its symptoms increase the risk of using cannabis.
34
what is the prevalence of schizophrenia in first degree relatives vs second degree relatives?
first degree is 6-17%
second degree is 2-6%
35
explain the results of adoption studies and schizophrenia (3)
- schizophrenia in adopted children is related to the presence of disease in the child’s biological relatives.
- Offspring of schizophrenia parents have the same risk of developing the disorder whether they are raised by the biological parents or others.
- Kety et al., 1968 found that 13% of the biological relatives of the adoptees with schizophrenia also had schizophrenia, but only 2% of the relatives of "normal" adoptees had schizophrenia.
36
what are the concordance rates in:
1. monozygotic twins
2. dizygotic twins
3. monozygotic twins reared apart
4. children of non-affected dizygotic twins
1. 50%
2. 15%
3. same concordance rates
4. high risk
37
what does the fact that the concordance rates in monozygotic twins (who share 100% of the genes) is not greater than 50% suggest?
involvement of non-genetic factors.
38
genetics appears to play a greater role as it is estimated that heritable elements (likely genes) account for about ____% risk for developing schizophrenia.
70-80
39
It has been believed that the susceptibility to schizophrenia is likely be due to genetic variations in multiple genes of small individual effects acting alone or in conjunction with other genes or environmental factors, like...
gene-gene and gene-environment interaction
40
what suggests that some cases are caused by single gene mutations?
recent discovery of copy number variations that increase risk to schizophrenia
41
genes implicated at the chromosomal loci (GWAS study) in schizophrenia play roles in what?
neurodevelopment, neurotransmision and synaptic plasticity
42
many of the genetic variants implicated in schizophrenia are also found to increase risk to neuropsychiatric disorder such as ____ and ____ disorder, thus suggesting a common genetic architecture of these illnesses.
autism; bipolar
43
While Kraepelin and Bleuler had recognized the importance of cognition in schizophrenia, they believed that patients' _____ was not impaired.
memory
44
why might kraepelin and bleuler believe that the memory was not impaired in schizophrenia?
patients did not have long-term memory deficit or rapid forgetting like one sees in Alzheimer's disease
45
what 7 lines of evidence support the idea that cognitive impairment is a core feature of schizophrenia?
1. Cognitive abnormalities in schizophrenia are highly prevalent. While similar cognitive deficits are also described in psychotic and non-psychotic affective disorders, they are often more severe and persistent in schizophrenia.
2. Cognitive decline is evident long before the onset of psychotic symptoms. There is considerable decline in cognitive function just before the onset of clinical symptoms.
3. Cognitive deficits are enduring and are observed even when clinical symptoms have remitted.
4. Milder neurocognitive abnormalities are observed in non-psychotic relatives of schizophrenia subjects.
5. Medication status, duration of illness, and severity of symptoms are not significantly correlated with cognitive decline. However, there is some evidence of an association between negative symptoms and the severity of cognitive deficits, particularly with those related to executive functions.
6. Cognitive deficits are better predictor of socio-occupational functional outcomes, than positive and negative symptoms.
7. Cognitive deficits generally are not ameliorated with current antipsychotic medications. This is currently an important unmet need in schizophrenia.
46
what are the types of cognitive deficits in schizophrenia?
generalized cognitive deficits, attention, EF, WM, episodic memory, semantic memory, verbal fluency, processing speed
47
how do you assess generalized impairment of cognitive functions?
IQ scores (performance and verbal)
48
Studies show that abnormalities in attentional processes may play only a ____ role in other cognitive dysfunctions present in schizophrenia.
small
49
Schizophrenia subjects show impairment in a higher order cognitive function of the _____ called the executive function.
prefrontal cortex
50
what does executive function include?
activities as planning,
decision-making, self-monitoring, behavioral flexibility and response control.
It allows for evaluation of circumstances and shifting of behavioral responses to changing environmental demands in pursuit of goal-directed behaviors.
51
schizophrenia patients have deficits in which tests used to evaluate EF?
Wisconsin Card Sort Test (WCST), Stroop test, and Trail Making Tests
52
why do schizophrenics show significant deficits in verbal fluency tasks?
Since these tasks demand setting up of an organized search strategy and switching between semantic categories, they also reflect on the executive dysfunction in this disorder
53
what deficit do some consider to be a key endophenotype of schizophrenia?
working memory
54
how is WM defined?
ultra-short-term and transient memory system for temporarily storing and manipulating information in the execution of complex cognitive tasks.
55
schizophrenia patients have deficits in which tests used to evaluate WM?
visuospatial delayed response tasks, and the N-back task.
56
how is processing speed affected in schizophrenics?
schizophrenia subjects show moderate deficits in the speed of performing simple tasks (e.g., taking greater number of trials to perform).
Its importance lies in the fact that many cognitive operations are dependent on processing speed to varying degrees.
57
Schizophrenia subjects consistently show deficits in tests of declarative memory, with severe impairments in immediate and delayed __ and ___ tests of declarative memory.
verbal; non-verbal
58
___ memory (i.e., memory that can be described) is one of the two forms of long-term memory, the other being ____ (memory that is evidenced by doing).
declarative; non-declarative/procedural
59
Declarative memory is further subdivided into ___ memory (memory of events, e.g., recalling a specific episode of life, or relating an event to a particular time and space) or ___ memory (general memory of facts without connection to time and place of learning, e.g., knowing what is the capital of Canada).
episodic; semantic
60
Non-declarative memory is divided into _____ (e.g., riding bicycle), learning by ____ (by hints or previous presentations) and ____ (association of stimulus and response).
skill learning priming; conditioning
61
(T/F): Non-declarative memory is relatively preserved in schizophrenia patients, with only mild impairment on tasks of procedural learning.
true
62
what functions do the frontal lobes have?
Cognitive functions and memory systems often involve multiple brain regions and subserved by distributed neural circuits, several aspects of attentional, executive function and working memory processes are critically dependent on the proper function of neurons within the prefrontal cortex.
63
what did PET and fMRI studies reveal about prefrontal activity in schizophrenia brains?
- revealed decreased prefrontal cortical activity in schizophrenia brains (so called hypofrontality).
- show reduced glucose utilization in the prefrontal cortex.
- this hypometabolism has been reported in both chronic and never medicated first episode patients.
64
how is evidence of hypofrontality obtained? (2)
when the subject is performing PFC related tasks such as WCST or CPT.
In most studies (but not all) schizophrenia subjects performing working memory tasks show less prefrontal activation (blood flow or glucose metabolism) than controls, even when their performance in the task is matched with that of controls.
65
whats the issue with the idea of hypofrontality in schizophrenia?
several fMRI studies of patients with schizophrenia have either failed to find hypofrontality or found greater activation in different regions of the prefrontal cortex (hyperfrontality).
Using N-back working memory task, Weinberger’s group demonstrated that healthy subjects’ prefrontal cortical activation increases as their working memory load increases in an inverted-U-shaped fashion.
Thus, subjects become hypofrontal when working memory capacity is exceeded.
66
what two theoretical possibilities should be considered about hypofrontality in schizophrenia?
1. patients and healthy subjects might operate on the same proximal part of the load-response curve, but patients might reach their capacity sooner (consistent with their limited working memory capacity, fall off the curve sooner, and thus appear to be hypofrontal compared with healthy subjects beyond this point).
2. schizophrenia patients and normal subjects operate on separate load-response curves with patients shifted to the left.
- Separate curves would predict that patients are hyperfrontal at relatively lower load and hypofrontal at higher load.
- Thus, hyperfrontality of schizophrenia patients at lower memory load (when their performance may be equal to normal subjects) may suggest an inefficiency of working memory information processing within the dorsolateral prefrontal cortex.
67
what are the functions of temporal lobes?
Temporal lobes, in particular the hippocampal formation, play a critical role in the formation of declarative memory as lesions to these structures characteristically lead to impairments in this form of memory.
68
what have fMRI studies shown about temporal activity in schizophrenics?
individuals with schizophrenia and high-risk subjects who progressed to psychosis have shown a hyper-metabolism (increased cerebral blood volume, CBV) in the CA1 area of the anterior hippocampus.
left CA1 hyperactivity negatively correlates with atrophy in the same area.
69
does hyperactivity drives atrophy or atrophy leads to hyperactivity?
- In some studies, hippocampal hyperactivity also positively correlates with psychotic symptoms.
- Compared to healthy controls that show a positive correlation between hippocampal CBV and cognitive task-related response, a negative correlation between hippocampal CBV and task-related responsivity is observed in schizophrenia subjects.
70
It is important to note that during performance of episodic memory tasks, schizophrenia subjects show ___ hippocampal activation.
reduced
71
Recent studies are also revealing that functional changes in the ___ and the ____ in schizophrenia may be due alterations in the functional connectivity between these two structures.
PFC; medial temporal lobes
72
people with schizophrenia may have deficits in the way they ____ a given stimulus and then ___ it
perceive; process
73
Schizophrenia patients show abnormal EEG recordings in response to specific stimuli, called ____.
ERPs
74
schizophrenics have a deficit in which ERP?
auditory mismatch negativity (MMN)
75
what is MMN?
MMN is a negative deflection in recordings when an oddball deviant stimulus is presented in a sequence of repetitive auditory stimuli
76
what do MMN look like in schizophrenia?
Schizophrenia patients show reduced amplitude of the negative potential.
77
Auditory MMN is generated within the primary and secondary ____ cortices with possible contributions from bilateral dorsolateral ___ cortices.
auditory; prefrontal
78
Since MMN is believed not to involve conscious and effortful attention, what is it used for?
it is used as an index of a preattentive form of sensory memory.
79
Schizophrenia subjects show deficits in tests of _____, for example, _____ (PPI).
sensori-motor integration; prepulse inhibition of startle
80
what is the prepulse inhibition of startle? (3)
Humans as well as animals normally respond with a startle reflex to suddenly presented strong sensory stimuli, e.g., loud tone.
However, if a weaker stimulus or tone (prepulse) is presented a few milliseconds before presentation of the strong stimulus, the response to the strong stimulus is attenuated.
The degree of PPI is a measure of sensorimotor integration (or gating), a kind of filtering mechanism protecting the brain from flooding with irrelevant stimuli.
81
This startle-inhibiting effect of the prepulse is ___ in people with schizophrenia, i.e., the patients continue to startle at high levels despite presentation of the prepulse
weaker
82
PPI deficits are frequent in schizophrenia, but why do they not have diagnostic value?
they also occur in stress-related disorders, alcoholism, neurodegenerative diseases, and autism
83
Although PPI deficit is not a specific marker of schizophrenia, it correlates with other measures of ____ control as well as ____ and thought disorder, and is considered as an _____
attentions; distractibility; endophenotype
84
The neural circuitry subserving PPI behavior involves nuclei in the brain __, ___, __ and ___, with projections to the ___.
The neural circuitry subserving PPI behavior involves nuclei in the brain stem, striatum, pallidum and thalamus, with projections to the cortex.
85
what does PPI strictly depend on (neurobiology) and how does this relate to schizophrenia?
PPI is critically dependent on striatal/nucleus accumbens dopamine transmission because dopamine receptor agonists exaggerate the deficits while antipsychotic drugs (dopamine D2 receptor antagonists) attenuate PPI deficits.
86
what is an endophenotype?
Intermediate phenotype which is physically measurable, is stable and can be linked to specific neurobiological mechanism or genetics.
87
what did Alzheimer do with schizophrenia?
studied possible cellular pathology in post-mortem schizophrenia brains, but found no characteristic features
88
what did plum declare about schizophrenia?
declared the disease as a "graveyard of neuropathology”
89
what are the gross anatomic changes in schizophrenia brains?
enlargement of ventricles (lateral and third ventricles) in schizophrenia brains (40% increase)
reduction in total brain volume (loss of grey matter)
thinning of brain white matter (myelinated nerve fibres)
reduction in volume of medial temporal lobe structures (i.e., hippocampus) and PFC
hippocampal atrophy
smaller volume of medic-dorsal thalamus
90
why isnt enlarged ventricles enough for a diagnosis of schizophrenia?
highly variable and present in other brain disorders as well
91
(T/F): ventricular volumes are progressive and get bigger with disease progression
false!
92
what is the interpretation of the non-progressive enlargement of ventricles?
ventricular enlargement is a “static” defect in schizophrenia and may be present at the beginning of the illness (or perhaps even before
93
Ventricular volume is seen to be ____ in the affected monozygotic twin compared to the unaffected twin, suggesting a greater role of non-shared environmental factors in this pathology.
However, observations that ventricular size in non-affected twin is still ___ than normal population, and that high-risk young individuals (by way of family history) also show ventricular enlargement argues for a role of heritable factors as well.
increased; larger
94
many imaging studies on subjects at high risk for schizophrenia reveal a progressive reduction in ____ and ____ well up to early adulthood. The rate of decrease appears to be greater around _____ age in high-risk subjects who convert to psychosis
hippocampal; cortical grey matter volume; adolescence
95
what may indicate a distinction between mechanisms of hippocampal volume reductions in schizophrenia and MDD?
A meta-analysis of 32 publications found that, in MDD, hippocampal volume is significantly reduced with greater than one lifetime major depressive episode or greater than 2 years of illness.
96
in contrast to developmental origins of hippocampal atrophy in ___ (i.e., a pre-existing risk factor), reduced hippocampal volume observed in ___ may result from the burden of illness.
schizophrenia; MDD
97
post mortem microscopic and neurohistochemical reveal neuronal abnormalities in which brain regions?
frontal and temporal cortices, thalamus, striatum and cerebellum
98
taken together, what do the studies reveal about neuronal abnormalities of schizophrenia?
something to do with altered synaptic development of frontal and/or temporal cortices
99
what are limitations of post mortem studies?
they are necessarily subject to many experimental confounds, such as length and severity of illness, medication history, lack of ideal control group, cause of death, agonal state, delay in tissue collection and storage
100
One thing that is generally accepted is that, despite cortical volume deficits, total neuron number does not appear to be _____ in schizophrenia brains
decreased
101
explain the results of Goldman-Rakic's study
Studies by Goldman-Rakic and colleagues have provided evidence of cortical neuronal atrophy (loss of neuropil either due to a loss of afferent fibres or shrinkage of dendritic arbors) rather than neuronal loss in schizophrenia.
This neuronal atrophy described in several cortical regions may result in increased neuronal density and can partly explain the reduction in cortical thickness.
102
what evidence supports Goldman-Rakic's view?
several reports of reductions in neuronal cell body size in the hippocampus and prefrontal cortex
replicable reductions in dendritic spine density in the layer 3 pyramidal neurons have been observed in several cortical regions, including the prefrontal cortex
103
what is Feinberg's hypothesis? what result supports it?
increased pruning (exaggerated) of existing synapses during adolescence may contribute to the onset of schizophrenia
Spines are principal regions for making synapses with incoming afferents of excitatory (glutamatergic) neurons
104
what is the alternate view to Feinberg's hypothesis?
as spines show experience and activity-dependent plasticity, the loss of dendritic spines in schizophrenia may be secondary to the lack of excitatory afferents coming from other brain regions such as the hippocampus or medio-dorsal thalamus.
105
it has also been argued that spine reduction in schizophrenia is due to mechanisms related to spine ___, rather than synaptic pruning.
formation
106
what cytoarchitectural anomalies have been found?
Changes in the laminar distribution of various subtypes of cortical subplate neurons and interneurons in the temporal and prefrontal cortices of some schizophrenia brains have been reported
suggestive of developmental errors of neuronal migration/lamination
107
what evidence do we have for synaptic disturbance in schizophrenia?
changes in a variety of neuronal and synaptic proteins and genes in post-mortem schizophrenia brains
Decrease in presynaptic proteins synaptophysin and SNAP-25 have been described in the prefrontal cortex of schizophrenia patients
reductions in dendritic marker MAP-2 and spine marker protein spinophilin
Changes in some other molecules that may be important for brain development and adult neural plasticity include NCAM, BDNF, neuregulin and dysbindin
108
what 4 lines of evidence support the association btw immune system dysfunction and schizophrenia?
1. immune system-related and major histocompatibility complex (MHC) genes are reported to be associated with schizophrenia
2. maternal infections increase risk for schizophrenia in the offspring
3. Direct evidence of alterations in proinflammatory cytokines has been observed in blood and CSF samples of patients with schizophrenia.
4. Studies report alterations in microglia in the brains of schizophrenia patients
109
what MHC locus gene is a critical mediator of schizophrenia pathology? explain it
complement 4 (C4) -- localized to neuronal synapses, dendrites, axons, cell bodies
Common C4 alleles associate with schizophrenia in proportion to their tendency to generate greater expression of C4A
C4A mRNA was shown to be overexpressed in the post-mortem brains of individuals with schizophrenia
110
explain the results of C4 in mice
A link of C4 with schizophrenia pathology comes from studies in mice where C4 (as well as other complement proteins such as C3 and C1q) is reported to mediate synaptic pruning during postnatal development.
These results implicate excessive complement activity may be a mechanism in the reduced numbers of spines/synapses observed in schizophrenia brains.
Research in animals supports this idea as overexpression of human C4A gene in mice resulted in reduced cortical synapse density, increased microglial engulfment of synapses and altered social, cognitive and anxiety-like behaviors
111
what are the results of the animal model on maternal infections and schizophrenia?
as offspring of rodent mothers administered lipopolysaccharide (LPS) or poly (I:C) (substances mimicking bacterial and viral infections, respectively) grow up to show behavioral and cellular changes related to schizophrenia
112
Levels of proinflammatory cytokines such as ____ (IL)-1β, IL-6 and _____ (TNFα) are found to be elevated in patients.
interleukin; Tumor necrosis factor a
113
what is the role of microglia?
the resident immune cells in the brain, provide a rapid and efficient response for counteracting pathogenic and other injuries to the brain
in circuit refinement and synaptic plasticity in the developing and adult brain through the phagocytic elimination (pruning) of axon terminals and dendritic spines.
114
what evidence supports alteration in microglia in schizophrenia?
Elevated microglial cell density (with an activated phenotype) has been observed in schizophrenia particularly in the frontal and temporal lobes.
Studies using the radioligand [11C]PBR28 (to label 18kD translocator-protein, TSPO expressed in microglia) and PET found increased binding of the ligand (suggestive of increased microglial activity) in schizophrenia subjects as well as young subjects at ultra high risk for psychosis.
115
what are the neurochemical abnormalities in schizophrenia?
exaggerated dopamine transmission (hyperdopaminergia) in schizophrenia.
positive (psychotic) features of schizophrenia are critically dependent on enhanced D-2 receptor mediated activity in the striatal/limbic DA regions of brain.
reduced DA transmission in the prefrontal cortex is believed to play a role in cognitive deficits observed in schizophrenia patients.
116
what is the original name for antipsychotic drugs?
neuroleptic drugs
117
what do antipsychotic drugs do?
bind to dopamine D2 receptors and work as antagonist of this receptor subtype.
schizophrenia was postulated to arise from an over-activity of striatal dopamine neurotransmission, specifically through D-2 receptors
118
what are the 4 key lines of evidence in support of the dopamine hypothesis?
1. effectiveness of antipsychotic drugs was directly related to their affinity for dopamine D-2 receptors.
2. observation that use/abuse of psychostimulant drugs (e.g., amphetamine and cocaine that increase synaptic DA levels) can lead to psychosis-like behaviors in healthy humans.
3. A number of studies directly measuring presynaptic dopamine synthesis and release, and availability of dopamine receptors have since confirmed an important role of dopamine in the pathophysiology of schizophrenia.
4. Implications of striatal and PFC DA alterations in positive, negative and cognitive dysfunctions in schizophrenia
119
The higher the affinity the drugs for D2, the ___ the doses of the drugs required to treat schizophrenia symptoms.
lower
120
psychostimulants exacerbate ___ symptoms in schizophrenia patients.
psychotic
121
what are 3 problems with the dopamine hypothesis?
- delayed effects of antipsychotics.
- Classical, typical antipsychotic drugs (that are selective D2 receptor antagonists) are not effective for negative symptoms. However, the newer atypical antipsychotics that target dopamine as well as other neurotransmitter receptors are efficacious against both positive and negative symptoms.
- A small percentage of patients are resistant to antipsychotic drugs.
122
how do you use PET to study DA uptake/synthetic capacity?
PET studies determine dopamine synthetic capacity by measuring the uptake of [18F]fluoro L-DOPA in the brain, reflecting more presynaptic dopamine terminals and/or increased activity of the decarboxylase enzyme.
123
what do post mortem studies show about D2R?
Post-mortem studies, using D2 receptor radioligand binding have reported increased dopamine D-2 receptor density in the caudate-putamen (striatum) of schizophrenia brains.
124
what is a potential confound with post-mortem studies looking at D2R?
studies show that increased D2 density is observed in patients with prior antipsychotic exposure, but rarely in those who are drug-naïve or untreated.
125
what are the two conclusions about the link btw D2R and schizophrenia?
D2-like receptors are likely unchanged in unmedicated schizophrenia patients; however, the possibility that increased D2 expression occurs in a sub-set of the patients could not be ruled out.
Another possibility that dopamine D2-like receptor function (as opposed to number) may be enhanced in patients remains to be properly determined.
126
Among the best direct evidence of increased dopamine transmission in schizophrenia are the studies on presynaptic dopamine ___ and ___.
synthesis and release
127
Higher [18F]DOPA levels reflect ____ presynaptic dopamine terminals and/or ___ activity of decarboxylase enzyme.
more; increased
128
A majority of such studies have shown ___ [18F]fluoro L-DOPA uptake in the striatum of schizophrenia patients, even those who were drug-naïve.
increased
129
One study showed that elevated striatal [18F]DOPA uptake also precedes the onset of ___ and correlates with greater ___ of prodromal symptoms and neuropsychological impairment.
psychosis; severity
130
(T/F): increased presynaptic DA states is only reported in schizophrenics
false: reported in psychotic individuals with diagnoses other than schizophrenia, such as bipolar disorder and temporal lobe epilepsy.
131
Studies on DAT density in the striatum have found no consistent change in schizophrenia; however, what does it suggest?
it is suggested that increased DAT levels may exist within a subgroup of patients.
132
Several studies provide evidence of enhanced ___ (and also stress)-induced increase in striatal dopamine release in living schizophrenia patients
amphetamine
133
what is the rational behind the following study:
Investigators have employed SPECT and PET imaging respectively using [125I]IBZM or[11C] raclopride (D2/D3 receptor antagonists) to measure the D2-like receptor binding in two conditions: baseline (predrug) and following single amphetamine injection (low dose, 0.2 - 0.3 mg/kg).
The rationale is that dopamine released following amphetamine injection would compete with, and thus reduce, radioligand binding (amphetamine itself does not interfere with the ligand binding).
whaA decrease in radiotracer binding would thus reflect increased amount of dopamine release.
134
what was found in the study on amphetamine?
Using antipsychotic-naive or antipsychotic-withdrawn patients, it was shown that following amphetamine, there is greater decrease in radiotracer binding (in other words, greater release of dopamine) in the schizophrenia striata compared to the controls.
135
amphetamine-induced change in radiotracer binding correlated positively with BPRS (____) total symptom scores (indicating global symptomatology) in the patients but not in the controls.
Brief Psychiatric Rating Scale
136
PET studies showed _____ amphetamine-induced dopamine release in the PFC (DLPFC) and several extra-striatal and cortical regions.
reduced
137
There appears to be an ___ relationship between cortical and striatal DA in schizophrenia
inverse
138
what does the inverse relationship btw cortical and striatal DA underscore?
underscores the idea that dopamine abnormalities in schizophrenia are region-specific and calls for further studies examining mechanisms of such regionally specific alterations, i.e., “hyperdopaminergia” in specific parts of the striatum and “hypodopaminergia” in the PFC and other regions.
139
what is reward prediction error by DA?
the discrepancy between expected and received reward. Increased DA neuron firing and signaling occurs in response to a wide range of salient stimuli.
140
how does reward prediction error relate to schizophrenia?
suggested that increased striatal DA function in schizophrenia may lead to irrelevant stimuli being interpreted as meaningful, causing inappropriate associations of non-salient stimulus with prior expectations resulting in delusions and hallucinations.
141
DA neurons fire in response to stimuli that have been previously associated with a ___ and ___ behavior towards actions associated with the reward.
Increased ___ DA state may cause a reduced motivational influence of reward-associated stimuli as high background levels of DA signaling will reduce the signal-to-noise ratio of adaptive signaling.
reward; motivate; striatal
142
what is the role of PFC DA in WM performance?
Sustained firing of DLPFC neurons is thought to be a cellular basis of short-term buffers associated with working memory functions.
Among other mechanisms, a particular role of D1 receptors is noted for the regulation of sustained firing of DLPFC neurons during the delay phase of delayed-response tasks that require working memory.
D1R has an “inverted U” shaped effect on working memory performances - too much or too little D1 activity is bad.
143
Preclinical studies in animal models of striatal D2 overexpression show that excessive striatal DA may lead to ____ in cortical DA and associated cognitive symptoms
reductions
144
how does schizophrenia relate to glutamate?
deficient glutamate-mediated excitatory neurotransmission through the NMDA subtype of glutamate receptors
145
what is the evidence for the NMDAR hypo function hypothesis?
that a single low dose of an NMDA receptor antagonist such as phencyclidine (PCP) or ketamine produces "schizophrenia-like" symptoms in healthy individuals and profoundly exacerbates preexisting symptoms in patients with schizophrenia
NMDA antagonist-induced symptoms include positive and negative as well as cognitive.
In addition, PPI deficits and impairments in working memory have also been described in healthy volunteers receiving subanesthetic doses of ketamine.
146
what explanation is given for the lack of consensus regarding changes in GluR and receptor mRNAs?
It is suggested that either other components of NMDA receptor signaling may be affected or that changes in NMDA receptors or subunits may occur in specific subpopulations of neurons that is harder to detect.
147
What do animal studies tell us about the effects of NMDA receptor hypofunction?
NMDA receptor antagonists have been shown to produce cortical excitation in humans and behaving rodents.
Rodent studies have shown that antagonists of NMDA receptors predominately decrease the activity of putative GABA interneurons but, at a delayed rate, increase the firing rate of pyramidal neurons.
148
NMDA hypofunction on ___ neurons will lead to reduced excitation of those neurons by excitatory glutamate containing afferents.
However, if NMDA-R deficit occurs in ___ neurons, that may result in reduced excitation of ___ neurons by excitatory afferents.
pyramidal; GABA; GABA
149
Since GABA neurons normally inhibit pyramidal neurons, deficit of NMDA-R on GABA neurons may ultimately result in ___ (____) of pyramidal neurons.
disinhibition; hyperexcitation
150
what reliable changes in GABA markers are seen in post-mortem brains?
decrease in the protein and mRNA levels of the GABA synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67) has been reported in the DLPFC and other cortical and limbic regions.
The level of GAD65 another enzyme for GABA synthesis appears normal. In addition, the mRNA levels of the vesicular GABA transporter (vGAT, which regulates the loading of GABA into synaptic vesicles) is lower in the PFC of schizophrenia subjects.
151
The decrease of GAD67 is observed in a subset of GABA interneurons, notably the ____ (PV) containing GABA interneurons (more pronounced in ___ cells).
The level of PV mRNA and number of PV expressing neurons is also reduced in the ___ and ____ of schizophrenia subjects.
In the DLPFC, PV neuron density is ___, but GAD67 is markedly ___ in these neurons
parvabulmin; basket cells; PFC; hippocampus; normal; reduced
152
____ interneurons, which comprise approximately 45% of GABA neurons in the primate DLPFC, do not appear to be affected.
____, expressed in another class of interneurons, has been found to be reduced.
calretinin-containing; somatostatin
153
what are the characteristics of PV-interneurons?
comprise about 40% of cortical GABAergic interneuron population and represent a critical regulatory element in PFC physiology.
very high firing activity and each PV neuron makes synapses with many pyramidal neurons, thus, they strongly inhibit the excitability of PFC glutamate neurons.
They are a major class of fast spiking interneurons that play a role in PFC gamma oscillatory activity and synchronize the activity of excitatory pyramidal neurons, essential for working memory.
154
what are the two subtypes of PV interneurons?
chandelier cells and basket cells
155
what are chandelier cells?
axons of chandelier cells innervate the axon initial segment of pyramidal neurons near the site of action potential generation
In layer 2/4 of the DLPFC, a decrease in PV chandelier neuron presynaptic GABA membrane transporter (GAT1, the protein responsible for reuptake of released GABA into nerve terminals) is reported.
In addition, axon initial segment of the pyramidal neurons show increased postsynaptic GABAA α2 receptor protein
156
what are basket cells?
the basket cells innervate the cell body and proximal dendrites of pyramidal neurons
basket cells show pronounced GAD67 deficit in layer 3/4 of DLPFC schizophrenia subjects.
GAT1 protein levels do not appear to be altered in the axon terminals of basket cells suggesting that GABA uptake is not reduced in these terminals in contrast to chandelier terminal cartridges.
157
GABAergic inhibitory inputs from basket cells to pyramidal cells are ___; therefore post-synaptic GABA transmission is ___ in pyramidal cells of the DLPFC in schizophrenia.
reduced; weaker
158
the reduced GABAergic input in the DLPFC, by disinhibiting pyramidal neurons, may contribute to _______
reduced gamma oscillations and deficits in cognitive functions in schizophrenia.
159
what typical/classical antipsychotic drugs are not effective in schizophrenia?
chlorpromazine and haloperidol
160
what are the side effects of the typical antipsychotic drugs?
variety of movement disorder, e.g., Parkinsonism ( tremor, rigidity, and bradykinesia), dystonia ( contraction of muscles), akathisia (feeling of restlessness), and tardive dyskinesia (involuntary rapid, jerky (choreiform) movements primarily of tongue, jaw and fingers).
161
why are the side effects of typical antipsychotic drugs often called extrapyramidal side effects?
because the motor system involved in these (i.e., the basal ganglia) is outside the pyramidal system which includes cortical motor areas, and spinal pyramidal tracts.
162
which antipsychotic drug is highly effective in alleviating psychotic symptoms in classical neuroleptic resistant patients?
clozapine
163
what is clozapine?
weak D2 blocker, and also has moderate affinity for dopamine D1, serotonin, muscarinic, and α1-adrenergic binding sites.
Clozapine shows little propensity to cause EPS.
164
what are the two classes of antipsychotic drugs?
typical antipsychotic drugs and atypical antipsychotic drugs
165
what are typical antipsychotic drugs?
effective in treating positive symptoms but not negative symptoms, and cause EPS.
This group includes Chlorpromazine, Haloperidol, Trifluoperazine, Fluphenazine etc
166
what are atypical antipsychotic drugs?
generally do not cause EPS, and have efficacy against both positive and negative symptoms.
This group includes drugs such as Clozapine, Risperidone, Olanzapine, Quetiapine, Ziprasidone and Aripiprazol.
they have as high an affinity for serotonin 5HT2 receptors as for dopamine.
167
what is interesting about aripiprazol?
partial agonist (i.e., weak stimulator) of D2 receptors.
This mechanism of action offers it advantage because the drug can reduce post-synaptic D2 transmission when endogenous DA levels are high (essentially functioning as antagonist), and increase D2 transmission when endogenous DA levels are very low -- it may act as DA “stabilizer”.
In addition, it may act at presynaptic D2 receptors to reduce DA release from DA nerve terminals.
168
What are the differences in the mechanisms of action of typical vs. atypical antipsychotic drugs?
Typical antipsychotic drugs cause c-fos activation in nucleus accumbens and caudate-putamen, however, atypical drugs induce c-fos in nucleus accumbens and prefrontal cortex.
It is thus believed that EPS liability of typical antipsychotic drugs may be due to blockade of dopamine receptors in the dorsal striatum (caudate-putamen), and the partial ameliorative effect of atypical drugs on negative symptoms may be related to their action on some receptor system in the prefrontal cortex.
169
give an example for the following statement: Some studies have shown that the level of in vivo occupancy of striatal dopamine D2 receptors determines the drugs’ effects on psychotic symptoms or on the EPS.
around 70% D2 occupancy is believed to lead to good antipsychotic response.
However, if the D2 occupancy exceeds 80%, the drug is likely to cause EPS side effects.
Most atypical antipsychotics, at clinically prescribed doses, occupy 70-80% of D2 receptors in vivo.
170
what is the neurodevelopment hypothesis of schizophrenia?
proposes that schizophrenia may be caused by a developmental abnormality in the brain that adversely affects normal development and maturation of neural circuits within temporal and prefrontal cortices.
The functional effects of presumed developmental abnormality remain dormant until adolescence when some neural systems, e.g., frontal lobes fully mature and the classic symptoms of the disease emerge.
171
what evidence is consistent with early neurodevelopmental abnormality in schizophrenia?
* Premorbid signs of psychomotor abnormalities.
* Environmental risk factors – e.g., maternal infections impact brain early development.
* Cellular/molecular changes in markers of early neurodevelopment (e.g., interstitial cells of white matter).
* Genes within the schizophrenia GWAS loci are enriched for neurodevelopmental processes and are expressed during fetal/neonatal ages.
172
what evidence is consistent with adolescent developmental abnormality?
* Characteristic age of onset (15-25).
* Prodromal symptoms and cognitive deterioration at adolescence.
* Decreased cortical and increased ventricular volume in high-risk subjects who convert to psychosis.
* Changes in cellular/molecular markers that mature at adolescence, e.g., PV GABA neurons, myelin.
173
how can we use animal models to study schizophrenia?
One can look at indices of dopamine transmission, amphetamine or stress-induced dopamine release and dopamine dependent behaviors in animals (e.g., locomotion, stereotypy), sensorimotor integration (e.g., PPI), working memory (e.g., delayed alternation), as well as social interactions.
one can look into various pathological changes described in schizophrenia.
174
animal studies do show is that, at the least, early developmental abnormality of a _____ in animals is related to the appearance of abnormal adult behaviors of relevance to schizophrenia.
temporal lobe structure
175
give an example of using manipulations of schizophrenia-related genes in rodents to report behavioral and neurochemical changes analogous to human schizophrenia
studies in transgenic mice modelling human chromosome 22q11.2 deletion, NMDA receptor subunit, DISC-1 and dysbindin-1 gene deleted knock out mice provide evidence for a role of these genes in schizophrenia and reveal possible mechanisms in the pathogenesis of the disorder.
