Biology of schizophrenia Flashcards
What biochemical changes are seen in schizophrenia?
- Decreased dopamine metabolites in cerebrospinal fluid
- Increased striatal D-2 receptors
- – Striatum = main terminal area of dopamine pathways
- Decreased mRNA for D-3 and D-4 receptors in cortical regions
- Decreased cortical glutamate
- – But not all studies have found this result
- Increased cortical glutamate receptors
- Decreased glutamate uptake sites in cingulate cortex
- Weak evidence for changes to serotonin in schizophrenia
What is the unified theory of the neurochemistry of schizophrenia?
- Core deficit in cortical glutamate systems
- – Much of the known pathology is in glutamatergic areas of cortex
- – Therapy targeted at glutamate systems
- Dopamine affects output from temporal cortical areas, where positive symptomatology is believed to originate
- – Therapy with dopamine antagonists treats positive symptoms
- Serotonin modulates function in many neurotransmitter systems, including glutamate and dopamine
- – Therapy with serotonin antagonists treats both positive and negative symptoms
What is the pharmacological treatment of schizophrenia?
- Chlorpromazine: drug used to treat surgical shock
— Patients reported a feeling of well-being, hence it was tried on psychotic patients
— Found to reduce psychotic symptoms
— It has since been found that chlorpromazine is an antagonist at dopamine receptors - Clozapine: atypical antipsychotic medication
— Good antipsychotic potency, but minimal motor side effects
— Effective in patients who are refractory to other antipsychotics
— Reduces negative symptoms
— But it causes leukopenia and agranulocytosis so the blood cell count must be monitored weekly – adds substantially to the patient inconvenience and cost
— It also causes excessive salivation and can cause transient hyperthermia and weight gain
— Used in patients who do not respond to other treatments
Currently: - First line acute and maintenance treatment generally uses atypical antipsychotics
- Use of typical antipsychotics mainly restricted to acute uncooperative patients where rapid onset is required
- Typical antipsychotics also used for non-compliant patients who require monthly injections of a depot antipsychotic
- But there are still a significant proportion of patients (~30%) who do not respond well to treatment
- Even in patients where antipsychotics are effective, discontinuing causes relapses at the rate of ~10% per month
- The adverse side effects of antipsychotic drugs means that many patients stop taking medication and relapse into psychosis
— Many patients select the risk of relapse rather than the subjectively unacceptable side effects
How may serotonin and dopamine interact in schizophrenia?
Kapur and Remington (1996)
- The serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain
- It also inhibits dopaminergic function at the terminal dopaminergic fields in the forebrain
- Serotonergic antagonists release the dopamine system from this inhibition
— This dis-inhibition of the dopamine system in the striatum may alleviate neuroleptic-induced extrapyramidal symptoms
• Concomitant serotonin antagonism could release endogenous dopamine in the striatum, which in turn may displace the neuroleptic from D2 sites in the striatum
• Or the serotonin blockade may elevate the threshold for extrapyramidal symptoms through the modulating influences on cholinergic or GABA-ergic mechanisms without a direct effect on D2 occupancy
— A similar disinhibition in the prefrontal cortex may ameliorate negative symptoms
• Negative symptoms may result from hypo-dopaminergic function in the prefrontal cortex
• Serotonin antagonism may lead to enhanced dopaminergic transmission in the prefrontal cortex by disinhibiting the dopaminergic system and this in turn may ameliorate negative symptoms
- However, the benefits of combined serotonergic-dopaminergic blockade may be observed in only a narrow dose range and may be lost with doses that produce suprathreshold dopaminergic blockade
What evidence is there to suggest that genetics play a role in the development of schizophrenia?
Gottesman, 1991
- 57 twin pairs studied (24 MZ, 33 DZ)
- Both of the twins had some sort of psychiatric abnormality, with one having a diagnosis of schizophrenia
- Age range: 19-64
- If both twins have schizophrenia: MZ = 42%, DZ=9%
- Genes appear to play a role in schizophrenia because the concordance rate is higher in MZ twins than DZ twins
- – But not 100% hence environmental factors must play a role
- Life events may cause epigenetic changes
What is the dopamine hypothesis?
- Early support = researchers learnt that medication that seemed to be helpful had the effect of reducing dopamine transmission
— Inferred dopamine cause of symptoms
— Indirect pharmacological evidence - Excessive dopamine activity
— Dopamine transmission: characteristic of neurons that link the midbrain with the cerebral cortex
— Role of dopamine receptors: guide attention and attention-related actions
— In schizophrenia, neurons that communicate using dopamine fire too often and transmit too many messages
— There could also be excessive numbers of dopamine receptors
— Dopamine antagonists do not treat negative symptoms – may indeed exacerbate them
— Changes in dopamine function may be a response to long term drug treatment - At best, the dopamine theory may account for positive symptoms
— Supported by the fact that antipsychotic drugs, which attempt to raise dopamine activity, are largely effective only for positive symptoms (Davey, 2008)
Davis et al (1991) - Attempted to explain the above by suggesting that excess dopamine activity may be limited to certain neural pathways, in particular the mesolimbic pathway
Cohen et al (1988) - Dopamine receptors in those diagnosed with schizophrenia are too sensitive
— Messages being transmitted by this system are sent too often and too easily - This could give rise to the disorganised thinking and communication styles typical of psychosis
- This is consistent with the fact that dopamine neutrons are known to play a critical role in controlling and guiding attention
What evidence is there for/against the dopamine hypothesis?
Haracz, 1982: AGAINST
- Further post-mortem research revealed increased dopamine receptors only found in those taking ‘anti-psychotic’ meds shortly before death
- Indirect pharmacological evidence still makes up the bulk of the support
— Despite extensive study of tissue samples obtained from schizophrenics
- Direct support is either uncompelling or has not been widely replicated
- The DA hypothesis appears to be limited in the range of patients to which it applies
— It is also restricted in theoretical scope
— It does not account for social aspects of schizophrenia
- Some of the differences most consistently found can be explained by effects of medication
- People’s experiences impact on neurotransmission and brain structure
— The traumagenic neurodevelopmental model of psychosis
Cromby, 2013 AGAINST
- Excesses of dopamine are not found in all people given a diagnosis of schizophrenia
- Dopamine excesses are found in people given many other diagnoses
— Bentall 2003
- Excessive dopamine is neither necessary nor sufficient as a cause of the experiences associated with a diagnosis of schizophrenia, nor is it exclusively associated with this diagnosis
- Amongst people given a diagnosis of schizophrenia, dopamine levels are only excessive at times when they are most distressed
— Bentall 2003
Gray (1995) FOR
- The release of dopamine from 10 terminals in the nucleus accumbens, in interaction with the projection to nucleus accumbens from the retrohippocampal region, is closely related to stimulus salience
— It may also be related to the heightened states of awareness reported by schizophrenics
Seeman and Kapur, 2001 FOR
- Post-mortem studies have found increased levels of dopamine and significantly more dopamine receptors in the brains of deceased schizophrenia sufferers
Carlsson, 2001 FOR
- Brain imaging studies have indicated that individuals diagnosed with schizophrenia show excessive levels of dopamine released from areas of the brain such as the basal ganglia
Angrist, Lee and Gershon (1974) FOR
- It was noticed that there was a strong link between the excessive use of amphetamines and a syndrome known as amphetamine psychosis
- When taken in high doses for long periods of time, amphetamines produce behavioural symptoms in humans and animals that closely resemble symptoms of psychosis
Faustman (1995) FOR
- Subsequently we have learned that amphetamines produce these disturbed behaviour patterns by increasing brain dopamine activity
- Giving amphetamines to those diagnosed with schizophrenia actually increases the severity of their symptoms
Goldsmith, Shapiro and Joyce (1997)
- Imaging studies have confirmed that individuals diagnosed with schizophrenia have more dopamine receptors in the branin, and that these are often more sensitive than those receptors found in non-sufferers
Sanislow and Carson, 2001 AGAINST
- Antipsychotic drugs do not start having an effect on symptoms until about 6 weeks after treatment has commenced
- This is unusual, because antipsychotic drugs are known to start blocking dopamine receptors in the brain within hours of administration, so we would expect improvement to be immediate
Nordstrom et al (1995) AGAINST
- Many new antipsychotic drugs are effective despite having only a minimal effect on brain dopamine levels, or appear to be effective because they block not only dopamine receptors but also serotonin receptors
