Psychosis Flashcards
is schizophrenia rare?
no 1 in 100 people have it
same prevalence as epilepsy, coeliac and OCD
what is the definition of psychosis?
psychosis is an umbrella term for conditions where there has been a loss of contact with reality
schizophrenia is a CAUSE of psychosis
why is schizophrenia important?
it is not rare and many people dont make full recovery
what are some life changing consequences of schizophrenia?
social isolation
stigma
reduced likelihood of finding work/partner
reduced life expectancy by 13-15 years
high risk of suicide
is schizophrenia more common in men or women?
men especially in their 20s
what are some biological causes of schizophrenia
neurochemical - dopamine/glutamate
brain structure - volume changes grey matter> white or frontal lobe > others
genetics - it is highly heritable
neurodevelopmental - those born 32< have 2 fold increased risk because of low birth weight and lack of O2.
what are some psychological causes of schizophrenia
chronic daily stresses or significant life event (also half biological because of predispositions)
drugs (biological stress)
adverse childhood experiences like abuse, neglect
what are some social causes of schizophrenia
urban upbringing - more stress, around more people, more likely to struggle due to poverty
migration
what is the stress/vulnerability curve?
if someone is highly vulnerable to schizophrenia, it will only take a little bit of stress to push them over the threshold and present symptoms
if someone has low vulnerability, it would have to be a significant stressful life event to temporarily push one over the threshold
or accumulated stresses
what is the bucket analogy of psychosis?
life stresses fill the bucket with water, if bucket overflows psychotic experiences may occur but if someone is able to cope well with stress, it is as if there is a tap at the bottom to relieve the pressure
what are some positive symptoms of schizophrenia
disorganised thoughts (incoherent and illogical)
delusions (false beliefs despite evidence
hallucinations (abnormal perception of senses)
unusual behaviour
what are some negative symptoms of schizophrenia
poverty of thought (not many thoughts, AFFECT (no emotional reaction to things)
leads to social + emotional withdrawl, ANHEDONIA (lack of enjoyment) and AVOLITION (lack of motivation)
what are some cognitive symptoms of schizophrenia
attention
memory (episodic and working)
executive function
decision making
what are some affective symptoms of schizophrenia
dysphoria and depression
how is schizophrenia diagnosed in the ICD-11 manual?
2+ of the following symptoms for 1 month or more
- persistent delusions
- persistent hallucinations
- disorganised thinking (tangentiality and incoherent speech when severe)
- experience of influence, passivity or control e.g ones impulses and thoughts are not generated by oneself but placed in mind by others
- negative symptoms
- grossly disorganised behaviour
- psychomotor disturbances (catatonic restlessness, agitation, negativism)
what is the most common form of hallucination
auditory
what is an example of delusions
grandiose delusions e.g claiming you are the president when you are not or that you have extraordinary talent
persecutory delusions e.g the neighbours are spying on them or the police want to torture them
do people with schizophrenia recognise they have an illness?
no and this is very common
how are people with schizophrenia assessed?
history, mental state examination, risk assessment, urine drug screen
based on clinical suspicion, follow with brain imaging - CT MRI
how is treatment of schizophrenia approached?
the same way as its causes
the biopsychosocial model
what is the biological treatment of schizophrenia?
antipsychotics
protect against relapse in short medium and long term
1st generation or newer 2nd generation
what are some 1st generation antipsychotics
chlorpromazine
haloperidol
what are some 2nd generation antipsychotics
clozapine
amisulpride
olanzapine
what is the distinction between typical and atypical antipsychotics
based on incidence of extrapyramidal side effects
efficacy in treatment of resistant patients
efficacy against negative symptoms
what are some side effects of antipsychotics
sedation
weight gain
extrapyramidal symptoms (similar to Parkinsons symptoms - restlessness, muscles contracting involuntarily)
hyperglycaemia
what are the adherence rates for antipsychotics
fall off with time
the relationship of prescriber and patient is important
falls by 25% within 10 days, 50% within 1 year and 75% within 2 years
what are some additional risks of clozapine?
agranulocytosis (lack of white blood cells and neutrophil, bad immune system, risk of sepsis so need regular blood tests and monitoring)
paralytic ileus (motor activity of bowel is impaired)
sedating
cardiomyopathy
how is schizophrenia treated psychologically
support to reduce stress
directed at individual or family
CBT or family therapy
what are some social treatments of schizophrenia
rehabilitation
occupational therapy
independent living/social support/ residential care
driving
community mental health team
what do psychological and social treatments focus on
functioning and social inclusion
what is the key to schizophrenia recovery
early diagnosis and access to treatment
recovery is NOT just full resolution of symptoms
how severe can schizophrenia be
varies there could be one episode with no impairment
or impairment after first episode with subsequent exacerbation and no return to normality
what is in the future of schizophrenia research?
focus on genetics - identify those at highest risk
CBT based technological therapies e.g avatar therapy - therapist builds avatar of person (AI) voice and gets them to communicate with it to take control of their thoughts
which delusion/belief is the most damaging
that people are dangerous because it can stop people getting care and treatment
what are the 3 stages of schizophrenia
prodromal
acute
residual
explain the 3 stages of schizophrenia
prodromal - stage before clinical symptoms e.g depression, mood swing, sleep disturbances
acute phase - psychosis symptoms
residual phase - active symptoms fade, moreso negative symptoms
how do patients rationalise auditory hallucinations
aliens or god
outline genetic causes of schizophrenia
there is clear genetic link, but not just one gene or simple inheritance
in monozygotic twins - 48% chance - so genes cant be the only factor
128 common single nucleotide polymorphisms e.g C to an A switch
what has the highest genetic risk associated with schizophrenia?
deletion of 30 genes on chromosome 22 (30% of patients) 22q11 deletion syndrome
genes linked to neurodevelopment e.g myelination, neuronal migration
synaptic plasticity genes
genes linked to dopamine signalling
what are some environmental causes of schizophrenia?
family stress, poor social interactions, poor maternal nutrition and infections/viruses at early age
trauma
genetic makeup combines with non-genetic factors
what are some structural abnormalities of the brain present in schizophrenia?
enlargement of cerebral ventricles (production of CSF, ion regulation, enlargement correlates with episodes)
changes in gyrification
decrease in grey matter volume
what type of cause is the loss of synapses
developmental
NOT neurodegenerative
why is decreased grey matter volume consequential?
grey matter contains neuronal soma and synapses
layer 5 pyramidal neurones which are critical and make up most of the cortical neurones
what are some structural abnormalities of the prefrontal cortex associated with schizophrenia?
decreased dendritic field size - 40% of layer 5 pyramidal neurones in human post mortem schizo brains
impacts cognitive function
decreased spine density in pyramidal neurones
reduced hippocampus size
disorganisation in CA2 area
what 3 neurotransmitters are associated with schizophrenia
dopamine
glutamate
gaba
who found the dopamine hypothesis
solomon snyder and phillip seeman
what is the evidence for the dopamine hypothesis
drugs that increase DA e.g amphetamine cause psychosis
- suggests psychosis is linked to having too much dopamine but this is too simplistic
what are the 2 main dopamine pathways affected?
A10 - ventral tegmental area (VTA) that goes up to cortex
A9 - substantia nigra (motor pathway)
what 4 pathways does the new dopamine hypothesis contain
mesolimbic DA pathway
mesocortical DA pathwway
nigrostriatal DA pathway
tuberinfundibular DA pathway
outline the mesolimbic dopamine pathway
neurons in VTA project to septum, amygdala, hippocampus and frontal cortex
this system is HYPERACTIVE in schizophrenia - which accounts for positive symptoms
outline the mesocortical dopamine pathway
neurons in VTA project to neocortex (prefrontal cortex)
proposed this system is HYPOACTIVE - account for negative symptoms
outline the nigrostriatal dopamine pathway
neurons in substantia nigra project to dorsal striatum (part of extrapyramidal motor system - initiation and control of movement)
outline the tuberinfundibular dopamine pathway
hypothalamus - anterior pituitary gland inhibits PROLACTIN - tonic inhibition of lactation
DA is released into perivascular spaces and taken up by capillaries, transported to pituitary gland and acts on cells to inhibit release of prolactin which regulates milk production in lactating mammals - important for later side effects
outline how glutamate transmission can cause schizophrenia
genes implicated in schizophrenia are linked to NMDA receptor
and drugs that block NMDA receptor can induce psychosis e.g ketamine and PCP (phencyclidine)
how does NMDA receptor affect schizophrenia
HYPOfunction due to lowered glutamate
hypothesis is that hypofunctional NMDARs on GABA interneurons (parvalbumin) lead to changes in corticla network oscillations
- and studies show schizophrenic people have reduced parvalbumin
also metanalaysis found decreases in GluN1 mRNA
outline GABA neurotransmitter
inhibitory neurotransmitter 5 subunits around central pole, 20 combinations expressed most commonly alpha 1 beta 2 gamma 2
how does GABA neurotransmission affect schizophrenia
GABA affinity desensitisation leads to inhibition of glutaminergic pyramidal neurones and so loss of synchronous cortical activity
this decreases parvalbumin (Ca2+ binding protein) in hippocampus and prefrontal cortex so they do not function properly.
outline the link between parvalbumin cells and perineuronal nets
PNN is an extracellular matrix which forms net around PV cells to keep them locked in place
WFA labels PNN - neuroprotection and stabilise synaptic connections
what happens to the perineuronal nets and parvalbumin cells in schizophrenia?
the density of PNNs increases in PFC until early adulthood
but in schizophrenia there is a significant decrease in PNN in layers 3 and 5 of the prefrontal cortex
so PNN could affect PV cell function and plasticity
what is the link between GABA and NMDA in schizophrenia?
interneurons fire more rapidly than pyramidal cell so they are powerful inhibitors to them
if someone takes ketamine/is schizophrenic NMDA receptors are preferentially blocked on parvalbumin interneurons
= reduced excitatory drive , not as much firing , pyramidal cell is no longer inhibited so fires FAST (abnormal)
= NMDA hypofunction
what is the link between GABA and glutamate in schizophrenia
they have an EXCITATION INHIBITION balance - this may drive some of the dopamine changes as they are all interconnected
too much excitation in pyramidal cells - projects in complex ways that are not fully understood but disrupts the system
what is the role of neuroinflammation in schizophrenia
neuroinflammation is responsible for the loss of grey matter in the pre frontal cortex - but this is not unique to schizophrenia
how does neuroinflammation happen
microglia and astrocytes activated (change shape), microglia release pro-inflammatory cytokines (IL-6, IL-10) and remove damaged cells
too many activated microglia and high serum inflammatory amateurs can cause loss of grey matter by microglia engulfing synapses and healthy cells
what can be a day to day cause of cortical inflammation
traffic-related air pollution can alter brain development and increase risk of schizophrenia
what affects schizophrenic people more - psychosis or cognitive dysfunction
cognitive dysfunction because psychosis is managed and treatable but the other symptoms affect people day to day and ability to function in society
what are cognitive abnormalities briefly
possibly the core feature of the disease
disruption in information processing/sensory perception
deficits in attention, STM and behavioural flexibility
are current treatments effective to cognitive abnormalities
no
what is the disconnection hypothesis?
pathology arises from disruptions in connectivity and communication of multiple brain areas rather than one alone and breakdown/dysregulation of neuronal circuits controlling cognitive, emotional and perceptual functions.
how is working memory defined
the ability to transiently maintain and manipulate a limited amount of information to guide thought/behaviour
what is an example of a working memory task?
match to sample task with dots - replicate which dots are coloured in after a 90s delay
the task depends on sustained firing of PFC pyramidal cells
why and how is working memory affected in schizophrenia?
it reduces accuracy and increases response time in tasks, probably to do with PFC activation from pyramidal cells
and WM deficits will lead to deficits in other cognitive functions
how will schizophrenics perform on the Wisconsin card sorting task?
they have to match test card to target, but the rules change
they do poorly, as they will learn the task but then get stuck and want to stick to original rule (perseverative errors)
how is the auditory cortex involved in schizophrenia?
generate auditory hallucinations - illusion is generated by thoughts coming from outside
what role does the parietal lobe play in schizophrenia
integrated sensory inputs
what role does the occipital lobe play in schizophrenia
info about visual world, disturbances cause difficulties in interpreting complex images and recognising motion
what role does the hippocampus have in schizophrenia
mediates learning and memory and this is impaired
what role does the limbic system play in schizophrenia
involved in emotion so leads to agitation in schiz
what role does the frontal lobe have in schizophrenia
critical to problem solving - in schiz have difficulty in planning and organising thougths
what role do the basal ganglia play in schizophrenia
involved in movement and emotion
contirbute to hallucinations and paranoia - side effects of drugs
how are network oscillations in the brain recorded?
EEG - different frequencies record activity from pyramidal cells under cortex via electrodes
power spectra - shows how big the oscillation is
what are gamma frequency oscillations involved in?
learning and working memory and sensory processing
30-80 Hz
what are the 2 types of beta/gamma oscillations
- sensory evoked beta-gamma activity
- background - spontaneous beta/gamma activity
what are network oscillations like in schizophrenia
there is increased background oscillation noise especially during specific tasks
gamma activity in delay period is reduced also
how is schizophrenic patients visual perception altered?
faces are important to the brain but schizophrenic people have decreased long range synchrony at 20-30Hz in response to Mooney faces
explain hallucinations in terms of oscillations
associated with increase in gamma in sensory areas
increase in long range synchrony
reduced interactions between brain regions means cannot process images normally
what changes are replicated in mouse schiz models?
changes in PNN
changes in glial cell activation
changes in PV neurons
pyramidal cell spines
what would you treat the rodent model with?
ketamine /PCP
how would you manipulate a schiz mouse model environmentally?
take away from mother and give to another mother (cross-fostered)
isolated rearing (take mother away for hours to induce stress)
neuroinflammation - give mother injection while pregnant to induce inflammatory response
which gene is disrupted in schiz
DISC1
22q11
how would you model positive symptoms on rodent
hyperactivity
induced locomotor
increase in stereotypic behaviours like rearing excessive grooming or eating
how would you model the negative symptoms on rodent?
social interaction test
see if it goes to see other mouse in chamber - abnormal if it doesnt
how would you model cognitive deficits on rodent model
spatial working memory
T maze - containing food and the location of food changes need to remember the alternate one to find food
what happens to PV cells after treatment with ketamine (NMDA antagonist)
after 5 days cells have not died but just no longer contain parvalbumin and even weeks after the cells dont recover
this is reversed in rat prelimbic cortex by clozapine treatment which restores PV and protects against loss
oscillations between which brain areas are impaired in schizophrenia?
hippocampus and PFC
they are not coherent or synchronised
what happened to the transgenic mouse model which had 22q11 deletion syndrome?
reduced firing of PV interneurones
reduced synchrony of activity
but adding neuregulin peptide imporved cell firing and reduced hyperactivity and memory because it binds ErB4 receptors largely specific for PV interneurone firing
does treatment of schizophrenia need improvement and why?
yes antipsychotics have little effect on cognitive symptoms
compliance is difficult as antipsychotics need to be taken for years and side effects are bad
issues with pregnancy
what are ‘typical’ antipsychotics (1st gen)
chlorpromazine, haloperidol
need to block 60-70% of D2 receptors for effect
extrapyramidal side effects seen when >80% block
block dopamine in nigrostriatal pathway - can cause Parkinsonism tremor and loss of facial expression
outline atypical antipsychotics (2nd gen)
clozapine
risperidone
better for EPS side effects
but clozapine associated with agranulocytosis
better for negative symptom treatment
low affinity for D2 receptor, higher for D3 and D4
clozapine has higher affinity for d2 in cortex than striatum
what is the time course for response to drug therapy
1-3 days = decreased agitation, hostility and anxiety
1-2 weeks = improvement in socialisation, self care and mood
3-6 weeks = improvement in disordered thoughts delusions and hallucinations
what are some D2 mediated side effects of antipsychotics
galactorrhea - milk produced from breast unrelated to pregnancy
gynaecomastea - increase in amount of breast gland tissue in men
for tuberinfundibulnar pathway - prolactin release and milk production
what are some histamine mediated side effects of antipsychotics
sedation and weight gain
what are some M1 (muscarinic acetylcholine) mediated side effects of antipsychotics
dry mouth, blurred vision, constipation and urinary retention
what are some noradrenergic mediated side effects of antipsychotics
postural hypotension
what are new schizophrenia treatments focused on
correcting the E-I imbalance
