Schizophrenia Flashcards
Names some psychotomimetics
LSD and PCP
What is the number one cause of premature death among people with schizophrenia?
Suicide
(an estimated 10% to 13% of deaths)
Topics covered
- Symptoms and Causes
- Antipsychotics and the Dopamine Hypothesis
- Genetics and Beyond the Dopamine Hypothesis
- Followed by workshop on an exam question
LO
- Critically assess neurobiological hypotheses for schizophrenia
- Discuss the difficulties faced in treating schizophrenia
- Describe the main drugs used to treat schizophrenia and what is understood about their mode of action (how they work)
- Discuss limitations of the drugs used to treat schizophrenia
- Outline different experimental approaches used to study the neurobiological basis of schizophrenia
- Comment on how the prospects for understanding and treating the disorder might be improved in the future
The Swiss psychiatrist Bleuler in 1908, did an experiment on “fragmentation of cognitive processess and personality” what did the case history illustrate?
- onset in adolescence
- complex array of symptoms
- role of stress in precipitating illness
- episodic nature- some individuals may only experience one episode in their life where other may experience multiple over their lifetime
What is meant by a positive and negative symptom with schizoprenia?
Positive is an obvious symptom and negative is the effects of the positive and impacts on mood
What are the positive symptoms of Schizophrenia?
- hallucinations- mainly auditory (*’inner speech’)
- thought disorders
- stereotypes behaviours
What part of the brain is involved in working memory?
Working memory occurs in the prefrontal cortex and it is where you can hear your voice in your head when working things out for a short period of time
What is the area that is involved in speech processing and what lobe is this present in?
Broca’s area
Which is located in the frontal lobe
Are there different subsets of neurons depending on whether you are talking to yourself or someone else?
Yes
What are the negative symptomatic effects of schizophrenia?
- poverty of affect
- cognitive impairment
- temporal disorientation
Gaser et al 2004 Neuroanatomy of ‘Hearing Voices’: A Frontotemporal Brain Structural Abnormality Associated with Auditory Hallucinations in Schizophrenia Cerebral Cortex, Volume 14, Issue 1, 1 January 2004, Pages 91–96, https://doi.org/10.1093/cercor/bhg107
Other case studies on BB
Tandon et al Diognosis and symptoms of schizophrenia in DSMV
Tell me about the incidence of schizophrenia?
Consistent with a genetic component
Not just genetic or the incidence for identical twins would be close to 100%
What are the causes of Schizophrenia?
Genetic
Psychosocial
Stuctural brain damage
Viral infection
Tell me about how genetics can cause schizophrenia
Supported by high concordance rate for monozygotic twins (48%)
Polygenetic disorder
Disorder triggered by environmental stress
Or environment in the home? Tienari looked at this, babies adopted away from ‘normal’ or ‘schizophrenic’ mothers:
Tell me about how psychosocial effects can lead to schizophrenia
adolescent onset- stress can lead to onset
stress can precipitate illness
higher rate of relapse in ‘emotionally charged’ home environment
blunted cortisol response
How can structural brain damage lead to schizophrenia?
some studies (CAT Scans and MRI) show ventricular enlargement
decreased volume of temporal lobe (hippocampus)
BUT
no gliosis (therefore not neurodegenerative)- non-specific reactive change of glial cells in response to damage to the CNS
more common of lefties in schizophrenia population
is there an ‘early’ injury to the brain?
obstetric complication? What causes LH?
developmental abnormality?
Tell me about some of the cytoarchitectual abnormalities in the cortex with schizophrenia
decreased number of small neurons in superficial layers
increased numbers of large neurons in deeper layers
- Schematic diagram illustrating migration pathway of the majority of glutamatergic neurons, originating in the ventricular zone (VZ) of the pallium and radially migrating into the developing cerebral cortex (red arrows).
- The majority of GABAergic neurons are generated in the medial (MGE) and lateral gangionic eminence (LGE) and reach their final position by tangential migration via deep pathways and superficial cortical layers.
- (B) Glutamatergic neurons (marked in different shades of red) are generated in the VZ and migrate radially either by somal translocation or, at later phases, by locomotion along radial glial cells (light gray).
- Upon reaching the marginal zone (MZ) they detach and align on top of previously generated neurons of the cortical plate (CP), generating the “inside first—outside last” pattern of the cerebral cortex.
- The majority of GABAergic neurons (marked in different shades of blue) reach the cortex via tangential migration in the deep pathway within the subventricular zone (SVZ) or the superficial pathway in the MZ.
- Some GABAergic interneurons travel also within the subplate (SP).
Tell me about how viral infection could lead to schizoprenia
higher incidence in patients born in late winter or spring
hypothesis that exposure of mother to virus during second trimester increases risk of schizophrenia to the child
Cytokines in second trimester that increases the risk of schizophrenia
these causes/hypotheses concerning the underlying mechanisms for schizophrenia are not mutually exclusive
Summarise the causes of schizophrenia
Recap
Symptoms- positive and negative
Time course
Causes- synergy between genetic susceptibility and environment
Site of brain dysfunction?
State some other areas in the brain which are involved with schizophrenia
- Limbic structure
- Dominant cerebral hemisphere
- dorsal-lateral pre-frontal cortex
- Basal ganglia
Explain how the limbic system is involved with schizophrenia
Limbic structure of brain: decreased size of temporal lobe, increased activity during auditory hallucination
Hippocampus and temporal lobe= yellow and ventricles= grey
No gliosis observes in PM brain in patients with schizophrenia, decreased volume of hippocampus due to loss of dendrites instead
Explain how the dominant cerebral hemisphere could be involved with schizophrenia
Dysfunction of the dominant cerebral hemisphere
- Left hemisphere is specialised for verbal function
- In normal individuals this is shown by increased brain activity to the left side of the brain during a verbal task
- This lateralisation appears disrupted in schizophrenia
- Could be the underlying explanation for cognitive impairment in this disease
- More recent studies focusing on connectivity- mapping tracts using diffusion tensor imaging
Explain how the dorsal-lateral prefrontal cortex is involved with schizophrenia
Hypofunctionality of dorsal-lateral prefrontal cortex
Lower activity of dorsal -lateral prefrontal cortex in patients with schizophrenia and this is important for executive decision making
The hypofunctionality correlates with poor performance in specific cognitive tasks (like the card one shown above)
Horizontal brain scan of metabolic activity when individual has been asked to perform a certain task.
Blue indicates a thinning of the cortex, red appears a thickening of the cortex in right hand side diagram
Explain how the basal ganglia is involved with schizophrenia
(site of action of antipsychotics)
Extrapyramidal motor control and coordination
Meta-analysis demonstrated a functional activation topography in the basal ganglia. Patients with schizophrenia show a decrease in basal ganglia activity across studies
Based on what we have discussed previously, explain some of the current understandings about schizophrenia
- Genetic susceptibility is involved but environment can modulate expression
- Positive symptoms involve temporal lobe i.e., auditory hallucinations
- Negative symptoms involve prefrontal cortex i.e., poor cognitive performance
- Consider; what challenges does this present for therapy?
- To treat you need to address +ve and -ve symptoms
Tell me some drugs that are involved in schizophrenia
- Reserpine
- Amphetamine
- L-DOPA
- Chlorpromazine
Tell me about reserpine and schizophrenia
Reserpine is antipsychotic-
naturally occurring plant alkaloid, used in Indian medicine as an herbal remedy,
It has calming and antipsychotic action.
This drug depletes synaptic catecholamines by blocking the vesicular monoamine transporter (transports catecholamines back into the vesicles)
Tell me about Amphetamine and schizophrenia
Tell me about L-DOPA and schizophrenia
Levodopa is a prodrug that is converted to dopamine by DOPA decarboxylase and can cross the blood-brain barrier. When in the brain, levodopa is decarboxylated to dopamine and stimulates the dopaminergic receptors, thereby compensating for the depleted supply of endogenous dopamine seen in Parkinson’s disease
L-DOPA can trigger psychotic episodes- precursor for dopamine, replenishes the depletion of dopamine in the nigrostriatal pathway, psychotic side effects, increases brain dopamine can trigger psychosis
NOTE: L-DOPA= Levodopa
Tell me about Chlorpromazine and schizophrenia
Chlorpromazine-
promethazine is an antihistamine
looking at its derivatives which is chlorpromazine
has antipsychotic actions
What family is Chlorpromazine a part of, why is this the case?
Chlorpromazine is part of a group called major tranquilliser (aka antipsychotic or neuroleptic) due to its strong sedative effects.
Tell me about Chlorpromazines actions within the body
Carlsson won Nobel prize for dopamine at NT
Showed that chlorpromazine increased dopamine turnover in rate
Increased of dopamine metabolites in CSF such as HVA and DOPAC
Blocks pre- and post- synaptic receptors. By blocking the post- it blocks the feedback inhibition of dopamine release into nerve terminal which increases dopamine metabolites
Dopamine receptor antagonists cause catalepsy (state of inability caused by dopamine receptor blockage in the nigrostriatal pathway)- drug induced acute Parkinson’s like state
Chlorpromazine is a very effective antagonist of D2 dopamine receptors
Roto-rod experiment done on rats to test catalepsy
Does dopamine receptor blockade explain the antipsychotic action of chlorpromazine ?
Dopamine receptors are all GPCR and theres D1 and D2 families
These are then further subdivided D1–> D1 and D5 and D2–> D2, D3 and D4
D2 receptor is of interest
What is the dopamine hypothesis with schizophrenia?
The symptoms of schizophrenia are due to excess dopamine neurotransmission in mesolimbic and mesocortical regions of the brain
Projections of VTA are effects in schizophrenia
Is there increased dopaminergic transmission in schizophrenia?
Is there increased dopaminergic transmission in schizophrenia?
dopamine release?
no consistent evidence for increase in dopamine release
dopamine receptors?
measurements made in post-mortem brain show an increase in D2 receptors- however, this could be due to drug treatment
drug treatment can disrupt the normal signalling the brain which could affect PM studies
measurements in drug naive patients using PET do not show consistent increased levels of D2
Explain the dopamine hypothesis
The hypothesis suggests that an increase in dopamine leads to schizophrenia. However there is no evidence for increased dopammine release
OR
increased dopamine receptor number?
increased sensititivity?
The literature is extensive and conflicting
What is some evidence that goes against the dopamine hypothesis
So the hypothesis states that there is an increase in dopamine
but, some dopamne receptor subtypes decreased e.g., D1 in PFC
Even though some of the evidence of the dopamine hypothesis is a bit conflicting, what dopamine receptors are a good antipsychotic?
dopamine receptor blockers esp D2 are effective antipsychotics in the majority of patients
Tell me where the dopamine receptors D1 are expressed and what they are involved in
D1 dopamine receptors are expressed in the cortex and are involved in working memory. This is important for cognitive performance
Name a D1 receptor antagonist and what it is used as?
SCH23390 is a high selective D1 receptor antagonist. Used as a label to investigate D1 receptor density in individuals with schizophrenia via PET scanning. Showed decrease in D1 receptors in the cortex in those with schizophrenia. Could be a neurobiological correlate with poor cognitive performance
Recap
- Dopamine receptor antagonists are antipsychotic
- Formulation of dopamine hypothesis
- But no evidence for change in dopamine signalling in schizophrenia…
What are some discrepancies with the dopamine hypothesis?
Delay between onset of treatment and full benefit?
effects on plasma prolactin
results from PET scans
What do PET scan results show?
Pet shows ds receptors blocked by more than 70% within a few hours of treatment
Tell me about Prolactin release and dopamine?
Prolactin release is under inhibitory control of dopamine
Arcuate nucleus of hypothalamus (releases dopamine) –> portal blood supply in pituitary stalk –> anterior pituitary –> acts on lactotrophs in the anterior pituitary which release prolactin by acting on D2 dopamine receptors.
Measure prolactin levels and benefit to patient after initiation with treatment of antipsychotic there would be an increase in prolactin levels (however this takes a while for the clinical benefit to appear)
D2 receptor blockade is not directly linked to the benefits that patients experience
Tell me about dopamine release in the mesostriatal/mesolimbic and mesocortical neurones
Tell me the typical classes of Antipsychotics (neuroleptics) and an example for each.
What effect do each have on the dopamine receptors
Phenothiazines e.g., chlorpromazine
Thioxanthene’s e.g., Flupenthixil
Butyrophenones e.g., haloperidol
All the above are dopamine receptor antagonists
What are some the limitations of the antipsychotics?
not effective in all patients
only effective against positive symptoms
What are some of the side effects of the ‘typical’ antispychotics and what receptors are they due to?
weight gain (antihistamine)
sedation (antihistamine)
postural hypotension (alpha adrenoreceptor blockade)
atropine-like side effects
hyperprolactinaemia (D2)
rarer side effect: neuroleptic malignant syndrome- potentially life threatening (confusion, rigidity, confers from autonomic hypersensitivity)
What is the most limiting side effect of these antipsychotics
What are the chronic and acute effects of this?
most limiting side effects are the movement disorders (these occur in all patients and come about from dopamine receptors being blocked in the extrapyramidal motor pathway)
acute e.g., Parkinson like syndrome
chronic- tardive dyskinesia
What is the main characteristics of Tardive dyskinesia?
repetitive, purposeless movement (movement of tongue and lips, risk of chocking, not apparent when sleeping)
irreversible (even when off medication this is not improved)
What is thought to be the potential cause of Tardive dyskinesia?
Cause?- takes a while to develop, hypothesis is a dopamine receptor hypersensitivity (excessive dopaminergic signalling in extrapyramidal region)
What is a drug given that could cause Tardive dyskinesia an tell me about this drug?
Reglan is a metaclopromide
It is prescribed in the states as a treatment for heartburn
It is a D2 receptor antagonist
A side effect can be tardive dyskinesia
If Reglan is stopped being taken by the individual, do the symptoms of Tardive dyskinesia persist?
persists with drug withdrawal- reglan is metaclopromide, used for heartburn!!
As well as repetitive, purposefull movement, what other effects does Tardive dyskinesia have?
orafacial, problems with speech, eating, choking, absent in sleep
Studies on monkeys around Tardive dyskinesia
Study on monkeys treating with antipsychotics: Decrease in the enzyme, glutamic acid decarboxylase, in the striatum. Glutamic acid decarboxylase is the synthetic enzyme for GABA. In the striatum there are GABAergic inhibitory interneurons that are important in motor control. In these monkeys there was a loss of synthetic enzyme which is a markers for synthetic neurons
What are some of the recent advances in schizophrenia and the atypical antipsychotics?
less sedation
reportedly low incidence of movement disorders
reportedly more effective against negative symptoms
classes
Name some examples of some of the classes of drugs used to help treat the symptoms of schizophrenia
CLOZAPINE
QUETIAPINE
OLANZIPINE
RISPERIDONE
ARIPIPRAZOLE
ASENAFINE
PALIPERIDONE
Tell me about Clozapine
CLOZAPINE- first atypical antipsychotic to be discovered
Caused less sedation
lower incidence of movement disorder
more effective against negative symptoms.
The term alerting, as opposed to sedative, has been used to describe this drug
However, reports of fatalities were reported due to agranulocytosis (fatal form of anaemia) so was removed from use in clinic
Clozapine…
The receptor profile of Haloperidol
The receptor profile of clozapine
Where is the D4 receptor expressed?
In the limbic regions of the brain
Tell me about the receptors that clozapine blocks/ doesn’t block
Clozapine doesn’t block the D2 receptor
But blocks the 5-HT2 receptors and alpha adrenoreceptors
What receptors does Risperidone block?
Risperidone blocks D2-like and 5-HT2 receptors
Recap
Symptoms – positive & negative
Causes- multicomponent
Treatment – antipsychotics and the dopamine hypothesis
Side-effects
Clozapine- fewer EP side effects, pharmacology?
What are the genetic basis’ for schizophrenia?
Linkage analysis further implicated cortical dysfunction)
DISC-1
NEUREGULIN
CATECHOL-O-METHYL-TRANSFERASE
But note- hundreds of genetic susceptibility factors have been linked to schizophrenia
What is the insight into the genetic basis’ of schizophrenia provided by?
Insight provided by:
Association with chromosomal microdeletion syndrome
Rare familial variants of schizophrenia
Tell me about Velocardio facial syndrome (VCFS)?
Deletion of 1.5 to 3 Mb in chromosome 22 (includes roughly 30 genes)
Increased incidence of psychiatric disorders, including schizophrenia
Higher incidence of deletion in chromosome 22 in schizophrenic population
Tell me about a candidate gene for schizophrenia?
catechol-O-methyl-transferase (COMT)
Genetic evidence : The COMT gene is found in a region of the 22nd chromosome of the human genome which is shown in genetic linkage studies for harbouring schizophrenia genes. Individuals with a deletion in this region (1/ 4000 human births) have 30 times more likelihood of developing schizophrenia
metabolic enzyme for dopamine
What are the COMT alleles in humans?
Two COMT alleles in humans:
valine 108
methionine 108- less stable enzyme
What are the hypothesis’ about met-108 and Val-108?
hypothesis that met-108 gives rise to higher synaptic dopamine
but val108 is the allele that shows linkage with schizophrenia and impaired cognitive function
Where are the COMT genes expressed?
In cortical regions of the brain
Although COMT is expressed widely throughout the brain, it appears to play a particularly important role in dopamine flux in the prefrontal cortex.
How does this familial schizophrenia diagram provide clues…
Scottish family with inherited psychiatric disorders
Disrupted in schizophrenia= DISC-1
What can chromosomal translocation introduce?
DNA breaks
Whats a gene that is a possibly associated with dopamine impairments?
Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments.
Where is DISC-1 identified?
Identified in family that has chromosomal translocation
Tell me about DISC-1
increased expression during neuronal development
expressed in cortical neurones
interacts with several proteins e.g. NuDEL, LIS1
The DISC-1 interactome
What gene is there an interaction with, with DISC-1 that causes lissencephaly?
What other gene is there a linkage with, with schizophrenia?
Tell me about Neuregulin and schizophrenia
Linkage analysis and fine genetic mapping identified a locus on chromosome 8 as a risk factor for schizophrenia: The region encodes neuregulin
Neuregulin is a growth factor that interacts with a receptor* (ErbB) that regulates neuronal differentiation and migration
What have PM studies of the brain shown about Neuregulin?
Postmortem analysis of brain from schizophrenics has identified an increase in levels of mRNA for neuregulin
What is the current hypothesis about Neuregulin and schizophrenia?
Current hypothesis is that an increase in neuregulin signalling is a risk factor for schizophrenia (possibly by reducing the function of the glutamate receptor the NMDA receptor)
Remember- the glutamate-dependent control of subcortical systems
Hypothesis of schizophrenia
Summary
Evidence for involvement of PFC and subcortical dopamine
in the negative and positive symptoms of schizophrenia
PFC (pre-frontal cortex):
1. hypofunctionality in brain imaging
2. altered cytoarchitecture in PM brain
3. decreased D1 in PM brain
4. lesions in primates give negative symptoms
5. DISC1 and COMT highly expressed in cortex
6. DISC1 implicated in neuronal migration and interacts with proteins which are mutated in lissencephaly
indicates that there may be neurodevelopmental defect that
causes abnormality in organisation of cortical neurones
Antipsychotic block dopamine receptors
Conclusions
Need to…
increase understanding of the genetic basis for the disorder to get insight into the underlying mechanisms
inform development of new models for the disorder and facilitate improved therapies
understand the complex interaction between environmental and genetic susceptibility factors that lead to expression of the disorder
aim early and accurate diagnosis and the development of therapies that limit the severe impact of schizophrenia on the patient
