week 10 part 1 Flashcards
Define Schizophrenia
A disorder characterised by loss of contact with the environment
- Disintegration in the level of functioning in everyday life
- Disintegration of personality
- Expressed as a disorder of feeling, thought, perception and behaviour
What is the definition and schizophrenia studied by?
Behavioural neuroscience
When was it thought that schizophrenia was a disease of a mind?
Last 50 years
What is the prevalence of schizophrenia?
- Most common mental illness
2. 1-2% of the population
Who has schizophrenia?
- 12.5% 3rd-degree relatives
- 25% 2nd-degree relatives
- 50% 1st-degree relatives
What does demographics of schizophrenia tell us?
A little bit about the origin of the disease
Where is schizophrenia common in?
- All cultures, genders and race
2. Men tend to develop symptoms earlier
What is the peak onset of schizophrenia?
Age group: 18-25 years
What are the symptoms for schizophrenia
- Adapted from DSM-V
- Describe clinical symptoms of behaviour which are either an exaggerating of existence characteristics of trait or reduction or duration of behaviours
- Positive and Negative symptoms
What are the positive symptoms of schizophrenia?
- exaggerations or distortions of normal processes or behaviours
- Delusions
- Hallucination
- Disorganised thinking
- Inappropriate behaviour
- Catatonia
- Include cognitive and mood symptoms
What are the negative symptoms of schizophrenia?
- Flat effect - absence of normal behaviour or emotion
- Social withdrawal
- Absence of emotion and expression
- Reduced energy, motivation and activity
- poor hygiene
- Include cognitive and mood symptoms
Positive symptoms
- Delusion (often paranoid)
- Hallucinations
- Disorganised speech
- Disorganised or catatonic behaviour
Negative symptoms
- Social withdrawal
- Flat emotional response
- Anhedonia
- Lack of motivation
What are more responsive to therapeutic drugs?
Postive symptoms
Which symptom is more difficult to treat?
Negative symptoms
What does positive symptoms refer to?
Mental disturbances in the patient’s perception of reality that do not exist objectively
Hallucination
Tend to be in auditory mode rather visual mode
Take form of voices being heard in the head or thinking their thoughts are being broadcast
What is catatonic behaviour
- Abnormality of movement and behaviour due to disturbed mental state
- Withdrawn from society
What does negative symptoms refer to?
Mental abilities which the patient has lost or abilities that the patient can no longer perform
What is flat emotional response?
inappropriate response to emotion such as someone laughing when there is a funerial
What is anhedonia?
When a person doesn’t experience pleasure in anything
What are key symptoms of depression?
- Anhedonia
2. Lack of motivation
What is aetiology?
- Cause, or set of causes, or manner of causation of a disease or condition
What is the early stage of schizophrenia aetiology called?
Prenatal childhood
What is early stage (aetiology) of schizophrenia?
Genetic predisposition and gene expression + Environmental insult including viruses, toxins, poor nutrition, birth complications
give rise to neurodevelopmental abnormalities from conception to early adulthood including:
- neuron formation
- migration
- synaptogenesis
- pruning
- apoptosis
What is the latent stage of schizophrenia aetiology called?
Puberty adolescence
What is the latent stage (aetiology) of schizophrenia?
Early subtle signs predicting schizophrenia including:
- motor abnormalities
- Apathy
- Social withdrawal
- Deficit in attentional and information-processing task
What is late stage of schizophrenia aetiology called?
Young adulthood
What is the late stage (aetiology) of schizophrenia?
Excessive synaptic pruning in adolescence leads to abnormal neuronal connectivity and function + later environmental insult such as stress, substance use, and HPA axis dysfunction
lead to greater impairment of cognitive function including:
- Deficit in attention
- Memory
- Executive function
- Positive symptoms including hallucination, delusion, disorganization
- Worsening of negative symptoms including deficit in motivation and emotion, isolation and anhedonia
What is the theories on the origin of schizophrenia
- Dopamine Hypothesis
- Glutamate hypothesis
- Immunological theory
- Neural development hypothesis
- Membrane hypothesis
What is dopamine hypothesis?
Overstimulation of dopaminergic pathways in cortical and limbic areas
What is immunological theory?
Abnormal immunological finding in subgroup schizophrenic patients
- Neurodegeneration
- Viral Infections
- Microglial activation
What is Glutamate hypothesis?
NMDAR hypofunction
What was schizophrenia called in 1800?
Premature madness
What did Carlsson and Lindqvist establish?
- Dopaminergic transmission altered in schizophrenia
- Attempt to identify compound that help motor symptoms of PD
- Discovered antipsychotic drugs
What drugs had an effect on the dopaminergic system and all replicated psychotic symptoms of schizophrenia?
- Largactil (Chlorpromazine)
- Reserpine
- Amphetamine
What is Largactil?
Commonly produce dyskinesia , parkinsonism
What is largactil name given to?
Drug called Chlorpromazine which was initially developed in 1950 as a drug for anaesthesia - calming effects of individual
What is Reserpine?
Effective for treating psychosis
Block the re-uptake of dopamine and other monoamines
What is Amphetamine?
Increase synaptic monoamine levels
Can induce psychotic symptoms
What do all these drugs have?
High affinity for dopamine D2 receptor
What further supported the role of dopamine in mental function?
Amphetamines or L-dopa may lead to disturbances, mimicking paranoid schizophrenia
What do different receptors have?
Different distribution in the brain
What happens when D1 receptor bind to dopamine?
Produce excitatory effects
What happens in D2 receptor?
Produce inhibitory effect on neurotransmission of dopamine
What is the brain distribution of D1?
Predominantly cortical
What is the brain distribution of D2?
Predominantly subcortical/STRIATAL
What can the effects of abnormalities in dopamine function vary by?
Brain region
What does hypoactivity in one region explain?
Hyperactivity in another region which will explain positive and negative symptoms
Where are there drops in level of dopamine?
prefrontal cortex
What is the hypofunction on a feedback loop with?
Stratium
in normal state, where are there dopaminergic neurons?
Ventral tegmental area projecting to PFC and nucleus accumbens
what happens in schizophrenia state?
There is inhibitory feedback
sends reduced inhibitory signals to stratium
limbic system becomes hyperactive
Where was dopamine metabolites not universally elevated in?
- CSF
2. Serum of patients with schizophrenia
What was the paradox of dopamine metabolite measured?
Reduced in some patients with schizophrenia while still correlating with symptom severity and response to antipsychotic drugs
What was hypofrontality in these studies directly correlated with?
Low CSF dopamine metabolite levels
What does CSF dopamine metabolite level reflect?
cortical dopamine metabolism
What indicates low frontal dopamine levels?
The relationship between hypofrontality and low CSF dopamine metabolite levels
What did lesions of dopamine neurons in PFC result in?
Increased levels of dopamine and its metabolite and D2 receptor density in stratium
What did application of dopamine agonist to prefrontal areas reduce
Dopamine metabolite levels in the stratium
What is schizophrenia characterised by?
- Frontal hypodopaminergia resulting in stratial hyperdopaminergia
What did Davis et al hypothesise
gative symptoms of schizophrenia resulted from frontal hypodopaminergia, based on the similarities between the behavior exhibited by animals and humans with frontal lobe lesionsand the negative symptoms of schizophrenia
What did postive symptoms hypothesized to result from?
striatal hyperdopaminergia, based on the findings that higher dopamine metabolite levels are related to greater positive symptoms and response to antipsychotic drug treatment.
What is the rule for wisconsin card sorting?
- The number of item on the card
- The colour
- What the card actually is
What is positive symptoms due to?
Overactivity in mesolimbic symptoms
What are negative symptoms associated with?
Hypofrontality (reduced dopamine in the frontal cortex)
What is the prototypical compound for atypical antipsychotic?
Clozapine
What does atypical antipsychotics have
- A better therapeutic and side effect profile than the typical antipsychotics-1st generation (FEWER side-effects)
- Affinity for a number of receptors
- Lower affinity for the dopamine D2 receptor
What are examples of atypical antipsychotics?
- Clozapine - low motor disorders
- Olanzapine - very low
- Risperidone - low
- Quetiapine - very low
- Ziprasidone - very low
Glutamatergic models
are based upon the observation that the psychotomimetic agents such as phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptor
What do we need to consider when we consider it as a neurodevelopmental disease?
The process of maturation in the brain
What 3 things start from moment of fertilization?
- Neuronal proliferation
- Migration arborization
- Myelination
What is the cortical development in Schizophrenia?
- Reduced interneuron activity
- Excessive excitatory pruning
- Deficient myelination
step 1 of environment stress in schizophrenia?
The risk of people living in rural areas is taken as a baseline
step 2 of environment stress in schizophrenia
People living in large city are twice as likely to develop schizophrenia as people living in the countryside
step 3 of environment stress in schizophrenia
The risk of schizophrenia for people living in smaller cities is somewhere in between
step 4 of environment stress in schizophrenia
Children who move to city later in life have a lower risk than children who move to the city earlier in life
Who has greater risk of developing sz to those that are born in a different time of year
People that born in early spring
What increases the rate of mental health problems for individuals as young adults?
Poverty during early development
Family-level stress
– Parental stress – parental psychopathology – low parental warmth or investment – hostile and inconsistent parenting – child abuse and neglect.
Individual level stress
– stressful life events (financial)
– hypothalamic-pituitary-adrenal (HPA) axis changes → stress physiology altered
– poor prenatal health and birth outcomes → maternal stress / in-utro stress
– inadequate nutrition and toxin exposure
Poverty in adulthood
– Higher rates of depressive disorders, anxiety disorders, psychological distress, and suicide. → studies shows in certain underprivilege communities in London there was a greater risk for sz for depression and suicide than the larger population
Who has an increase risk to develop schizophrenia
Children and young adult that suffer from Asthma
What increases risk for SZ and Asthma?
- Maternal inflammation during pregnancy
- Increase activity of microglia in PET scans in young people predicts elevated risk to develop SZ.
- Microglia are also found to be increased when there is neuroinflammation
What is severity of schizophrenia linked to?
Activation of microglia
• Elevated inflammation during pregnancy or adolescence might increase risk for SZ
What is component 4 associated with?
excessive pruning of synapses and also with inflammation and activation of microglia
What is excessive synaptic pruning caused by?
Variant of C4 gene
What might trigger hyperactivation of microglia and an inflammatory phenotype of the brain
poverty or social isolation or the excessive consumption of drugs
post mortem brain
imbalances on dopamine concentration, been found to have imbalances on GABAergic synapses, been found to have activated microglia and been found to have higher level of inflammation
What is a poor model for schizophrenia?
Rodents
