Schizophrenia Flashcards
What are Schneider’s First Rank Symptoms
Delusion
Auditory hallucinations
Thought disorder; passivity of thought (withdrawal, insertion, broadcasting)
Passivity experiences (passivity of affect, passivity of impulse, passivity of volition, somatic passivity)
Describe the hallucinations in schizophrenia
Auditory
Visual hallucinations very rare; typically occurs in delirium or organic causes
Occasionally tactile
Not auditory misperceptions; it sounds like real speech in external space (command hallucination)
Describe the delusions in schizophrenia
Fixed rigidly held beliefs
Dominates thinking and is socially disabling
Often bizarre
Reason patient gives for belief important
Not eccentric ideas or suspicion; e.g. rigidly held belief that radio transmitter is implanted into ear
Describe the negative symptoms associated with schizophrenia
Persistent loss of usual activities and interests, apathy, blunted affect, poverty of speech
Social withdrawal, impaired attention, anhedonia, lethargy
Very disabling; not responsive to antipsychotic medication
Not due to mood disorder or antipsychotic SE (by definition)
If it was due to a mood disorder the patient would have schizoaffective disorder, not schizophrenia
Describe passivity phenomena associated with schizophrenia
Patients belief that they no longer control their actions, feelings or thoughts
External agent controlling them to act, feel or think
Describe Whitford’s theory of schizophrenia
Brain abnormalities and abnormal salience (hallucinations and delusions) and agency (passivity phenomena)
SZ arises because of a genetic trigger (e.g. sex hormone linked) in late adolescence/ early adulthood. For example, a trigger results in abnormal expression of oligodendrocyte linked genes during pre-pubertal myelination of the associated cortices
Myelin structurally abnormal (abnormal FA) and consequently there is abnormal ability to insulate axon membranes affecting the velocity of action potentials
Functional disconnections result in disruption of corollary discharge mechanisms
Self-generated actions/ thoughts/ speech not tagged as internally generated leading to first rank symptoms with an abnormal sense of agency
If brains response to constantly experiencing internally generated events such as unexpected external events is to increase DA noise; then hyperdopmanergia could be treatable by DA blockers
Major factors in determining whether a synapse survives peri-adolescent synaptic pruning is it synchronicity with other neurons. Abnormal myelination could result in increased synaptic loss = grey matter abnormalities
Is there a genetic link in schizophrenia when looking at adoption/ twin studies studies?
Yes; children of SZ mothers adopted soon after birth by non -SZ families have a 13% increase in likelihood of developing schizophrenia
There is no increased risk of developing SZ for children of non-SZ parents similarly adopted
% lifetime risk of SZ:
General pop; 2-3%
DZ twin; 16-17%
MZ twin/ both parents; 45%
What has been the problem with genetic studies in SZ?
Problem with replication between studies
Multiple genes each with very small effect
Molecular genetics explain a very small amount of variance seem
Good evidence for genetic abnormalities from family/ adoption studies but molecular genetic studies have not identified clinically useful findings for drug discovery
What white matter abnormalities are seen in SZ?
Biggest abnormalities in corona radiata and corpus callosum
Robust evidence for widespread white matter abnormalities
What is the corollary discharge hypothesis?
Theory of normal physiological mechanism which if abnormal would lead to symptoms
Corollary discharge theory:
Motor command from cortex feeds to the motor system which then feeds to the sensory system allowing for sensory re-afference and discrepancy
Alternative efference copy sent from the motor command to the forward model which acts to predict the sensory consequence of the motor system. Prepares the sensory feedback - corollary discharge (estimated sensory feedback).
Actual sensory feedback compared with predicted feedback (corollary discharge) to inform CNS about external actions. This acts to partially cancel out self generated sensation. The prediction “tags” external actions allowing discrimination from internal actions e.g. how you know the difference between external world movement vs self-generated eye movement
How can abnormal corollary discharge relate to the symptoms of SZ?
Inner speech/ thoughts are internalized - corollary discharge applies
Auditory hallucinations are due to a failure of corollary discharge connections due to impaired white matter tract integrity
From broca’s to wernickes there is a failure of connection
Auditory hallucinations are untagged sub vocal speech and therefore not recognized by the brain as self-generated
What is the experimental evidence for abnormal corollary discharge in SZ?
Very few studies
Relates to difficulty with funding in psychiatric disorders
What is passivity phenomena?
Experience that actions, thoughts and emotions are generated by outside agent
Means being controlled like a “robot”
Altered sense of agency in SZ hypothesised to be dysfunction of perception and action (e.g. corollary discharge mechanism) therefore faulty integration of prior knowledge and expectations with evidence
What are the 2 separate cues to sense of agency?
Sensorimotor system (corollary discharge) Meta cognitive system (interprets cues)
Physiological prediction deficit in sensorimotor function leads to distorted agency cues which modulates cognitive levels
How was this sense of agency and passivity phenomenon being related to abnormal corollary discharge and cognitive system tested?
Studying experimentally different timing cues to agency
Agency requires causal relationship; action precedes sensory and perceptual events
Subjects listened to a computer generated simple auditory sequence and reproduce it
Whilst reproducing there was 2 randomly ordered sound reproduction conditions;
1) self control; heard own undistorted tapping
2) external control; heard distorted different tapping
Asked if what they heard was self-produced or not
SZ pts tended to over-attribute auditory events to own actions
Tendency to attribute sensory events to own action most highly correlated with highest self ratings of clinical passivity phenomena
OPPOSITE of what was hypothesized
Interpreted to reflect secondary cognitive compensatory could explain this.
What experimental data is there to show that SZ patients are associated with a specific impairment of the predictive component mechanisms?
Voss; experiments as well as clinical observations show an enhanced rather than reduced sense of agency
Patients had to discriminate between predictive and retrospective mechanisms
Showed those with SZ have a specific impairment of prediction
Is there a link between action and effect?
Yes Predictively (Action predicted to generate a given effect) - corollary discharge Retrospectively (inference action caused effect - cognitive mechanism)
What is intentional binding?
Linkage with external effect - provides an implicit measure of the sense of agency. Has both predictive and retrospective components
For example, when key press is frequently followed by a tone; healthy subjects perceived the time of action shifted towards the anticipated tone, even when there was no tone delivered suggesting it was predicted
Shift in action awareness also occurred when the tone was not highly predictable but occurred, suggesting retrospective inferential processes
Describe the difference seen with predictive and retrospective components in intentional binding between controls and SZ
Controls; strong predictive component of intentional binding with minimal retrospective component
SZ; absent predictive component with strong retrospective component (postdiction)
Higher incidence of first rank sy, such as delusions and hallucinations are associated with a more reduced predictive component
Positive sy occur because the comparator lacks a predictive input. Even internally generated info such as ones own thoughts and intentions would be perceived as originating externally
What is a key mechanism underlying the sense of agency in SZ?
Association between ones action and external effect
Association is the experience of fluently controlling actions and external world
Such associations produce normal systematic distortions of time perception linked to voluntary action
Patients were generating imprecise predictions rather than no predictions
The strength of outcome prediction was not related to objective likelihood of the outcome predictions were equally strong in high and low probability conditions (implying aberrant DA signalling)
Are there any links between DA function and intentional binding?
Drug withdrawal study on patients with PD
PD off meds; same intentional binding
PD on meds; increased intentional binding
Associative learning paradigm modified blocking paradigm prediction error signals
Learning is only when there is unexpected high surprise events; increased intentional binding effect negatively correlated with schizotypy ratings
What is the brains response to constant internally generated internal events as unexpected external events?
Hyperdopaminergia
Disrupted oligodendrocyte growth in mice with reported hyperdopaminergia
What DA system is a critical component of sailence?
Mesolimbic DA
Psychosis is a state of aberrant salience
What is salience?
Process by which events and thoughts grab attention, and influence goal directed behaviour because of association with reward or punishment linked to concepts of value
What is the link of delusions and hallucinations with salience?
Delusions; beliefs with extremely high abnormal salience
Hallucinations; abnormal high salience of internal thoughts
What nT mediates salience acquisition and expression?
DA but it does not create the process; DA release is dependent on external stimuli which the DA system responds to to then modify the brain
What is the link of psychosis with DA?
Dysregulated DA transmission leading to stimulus independent release of DA
Dysregulated DA firing becomes a creator of “abnormal saliences” (psychotic symptoms)
How do antipsychotics work in linkage with salience?
Efficacious because they all share a common property of dampening DA function and therefore dampening salience (abnormal and normal)
Common psychological effect of antipsychotics is to dampen salience acquisition
Provide a physiological context of attenuated salience; reinforcement of importance or value of events
What is punishment avoidance associated with?
Indirect basal ganglia pathway and D2 receptors
Reward-learning is associated with direct basal ganglia pathway and D1 receptors
Do antipsychotics remove psychotic symptoms?
No; they attenuate the salience of distressing ideas and percepts over time
Attenuation of normal salience may in part account of the negative symptoms; antipsychotics do not treat these
What does the clinical efficacy of antipsychotic drugs rely on?
Ability to block D2 receptors; and therefore the indirect basal ganglia pathway
Is there instant uptake of antipsychotics into the basal ganglia?
No; it will occupy D2/3 receptors in a dose dependent manner
Describe the medication given in SZ and the downfalls associated with it
Antipsychotics; dopamine D2 blockade; positive symptoms
5-25%; unresponsive
5-10% intolerant (parkinsonism, akathisia, dyskinesia)
40-60%; non-compliant with oral meds
Depot; increased compliance, reduction in relapse rates
Continuous therapy far better than intermittent treatment
Traditional vs atypical?
Traditional; chlorpromazine, haloperidol
Atypical; clozapine, olanzapine, risperidone, quiteiapine
When is clozapine prescribed?
Failure to respond to 3 antipsychotics using an adequate dose for an adequate duration
Agranulocytosis; regular FBC required
Are there reliable predictors of outcome in SZ?
No; heterogenous disorder
Most pts become progressively and severely disabled
Chemical factors assoc with good prognosis:
Female, abrupt onset of illness, married, good premorbid social adjustment
FMHx of affective disorder, short duration of illness prior to tx
Good initial response to treatment, lack of neg sy, lack of cognitive impairment
No ventricular enlargement
When is the rates of suicide highest in SZ?
10%
Early in illness, males with chronic illness, tardive dyskinesia, unemployed
Previous high educational attainment, sudden stoppage of meds
Recent discharge from hospital
What causes the grey matter abnormalities seen in SZ?
Neutrophil elimination (not neuronal death) Most likely loss of dendritic abors and associated synaptic infrastructure Progressive over initial years of illness
What grey matter abnormalities have been observed in SZ brains?
Reduction in hippocampal volumes (similar to depression)
Amygdala
Thalamus
N. Acc
