Carlsson et al (1999) Flashcards
Carlsson et al (1999)
Aims and design A01
Aims:
1) Provide more of an explanation that simply the dopamine hypothesis (only tackles positive symptoms)
2) Look at the relationship between neurotransmitter levels; dopamine and glutamate interaction on the symptoms of SZ
3) Reviewing antipsychotic drugs that could be more effective, with fewer negative side effects
Design:
- Systematic review of 33 studies= 32 published, 1 unpublished
- Reading through and collating similar ideas to create own hypothesis about neurotransmission and SZ as part of his review
Carlsson et al (1999)
Procedure A01
-Reviewed the methods and findings of studies in the area they were looking at, and use the other studies and the data gathering studies to build a body of knowledge about the area of dopamine and SZ
Variety of sources investigated=
-Neuro-chemical levels in patients diagnosed with SZ
-Studies into drugs know to induce symptoms of psychosis (positive symptoms of SZ)
Evidence from Maghaddam and Adam 1998= their findings about the effects of the recreational drug ‘angel dust’- PCP. Knowing what PCP does at a neuronal level- we can infer what goes on in regard to neurotransmitter levels in the brain of a Schizophrenic
-Review of research using rodents to test neurotransmitter function, related to brain structure; specifically evidence from studies looking at mice and their behaviour (eg when given PCP)
-Studies with different types of SZ such as acute SZ and SZ in remission
-Studies using PET scanning methodology, when looking at neurotransmitter levels= radio active tracer specifically that binds to neurotransmitters in the brain- can identify the level of activity of the neurotransmitter
Carlsson et al (1999)
Results 1- Dopamine and Glutamate A01 part 1
Glutamate has a role in SZ:
Glutamate failure in the cerebral cortex= negative symptoms
Glutamate failure in Basal ganglia=positive symptoms
Reduction of glutamate in the brain causes psychotic symptoms; Hallucinations, delusions, cognitive disturbances, no flexibility in cognitive thinking
Explanation of how it may be glutamate deficiency not excess dopamine=
-PCP can lead to psychosis(SZ like symptoms), PCP blocks the glutamate receptors (specifically NMDA- a Glutamate receptor sub type) and limits glutamate by reducing the levels in the brain
-PCP leads to psychosis and blocks glutamate receptors, suggesting perhaps glutamate deficiency has a role in psychosis(positive symptom of SZ)
-Glutamate deficiency has consequences such as cognitive disturbances and loss of flexibility in cognitive thinking, and other behavioural aberrations which reflect negative SZ symptoms
-Therefore glutamate deficiency causes both positive and negative symptoms of SZ
Carlsson et al (1999)
Results 1- Dopamine and Glutamate A01 part 2
Interaction between dopamine and glutamate:
- There is a possibility if reduced pre synaptic dopamine function in SZ causes compensatory response of hypoglutamteriga- increased glutamate
- Reduced levels of glutamate associated with increased dopamine release, so glutamate and dopamine interact= Dopamine neurones seems to be controlled by glutamatergic neurones acting either as ‘breaks’ in mesocortical or ‘accelerators’ in mesolimbic
- It appears ‘break’ is most dominant, but not by much. However if amphetamine or something else raises dopamine suddenly, the reaction means strongly weighting the reaction to the break
- The explanation of how glutamate and dopamine affect one another, can explain the dopamine enhancement that comes from amphetamine in those with SZ. But there might be a glutamate deficiency, which might be the explanation rather than excess dopamine
Carlsson et al (1999)
Results 2- Thalamic Filter
Interaction between dopamine and glutamate pathways (both are antagonists) from the striatum (lower brain stem and cortex) relates to psychotic behaviour:
-The thalamus ‘filters off’ neurotransmitters coming out of the striatum- basal gang;is to stop the cerebral cortex from over loading
-2 pathways at work;
Indirect pathway= too much dopamine (hyperdopaminegia) or too little glutamate (hypoglutamatergia) reduces the protective influence of the thalamus(from sensory overload) which can lead to confusion or psychosis- positive symptoms
Direct pathway= Has the opposite effect, abnormal dopamine and glutamate levels will ‘excite’ the thalamus, preventing the stimulation of the cerebral cortex, predicted to link to negative symptoms
Carlsson et al (1999)
Results 3-Drug effectiveness part 1
Drugs acting on dopamine not considered valuable?
- A way of knowing how useful drugs are relating to dopamine availability; requires we find out more about how dopamine works
- Carlsson explains they have developed drugs/compound that can stabilise the dopaminergic system without lowering dopamine levels too far (concern being Parkinson-like symptoms)
- Some patients respond to some drugs better than others, and this might be because some peoples SZ is more dopaminergic and other symptoms are more glutamatergic
- ‘Treatment resistant patients’ don’t respond to typical antipsychotics which reduce dopamine might have a more glutamatergic condition instead
Carlsson et al (1999)
Results 3-Drug effectiveness part 2
Clozapine:
-Research has shown that clozapine is a highly effective drug treatment for SZ. It has both anti dopaminergic- reduces dopamine and anti serotoniergic properties; also alters serotonin by increasing it a specific receptors
-Highly effective in patients who previously had not responded to treatments because of the relationship between serotonin and glutamate
-The evidence could infer that some difficult to treat patients with SZ may belong to a sub group whose disorder may be better explained by hypoglutamatergia- reduced levels of glutamate
-It is proposed that the reciprocal integration occurs in the frontal cortex:
If serotonin= inhibited
Glutamate= inhibited
-Hence clozapine increases serotonin activity which in turn increases glutamate levels= reduction in negative symptoms and reduced dopamine improves positive symptoms
Carlsson et al (1999)
Results summary A01
1) Excess dopamine hypothesis is likely too simplistic= Carlsson et al mentions it’s unlikely dopamine if the only dysfunctional neurotransmitter in SZ, also dopamine changes may come from other changes in people with SZ.
-Excess dopamine at PSR= too simplistic, clear from review that it’s not just dopamine that produces SZ like symptoms
2)The review list noradrenaline, serotonin,acetylcholine, glutamate and GABA as likely NT to relate to SZ=Glutamate is the main NT focusing on in the review as having a role in SZ
Serotonin-Glutamate-Dopamine
=Trio of NT influencing one another to impact on SZ symptoms/brain functioning producing SZ symptoms
3)Dopamine is easier to study in the live brain that other NT= The reason for for this dopamine hypothesis is dopamine is easier to study, radioactive tracer which bind to dopamine strongly hold on long enough to see activity during PET scan
-Other NT radioactive tracers don’t bind well- so can’t see if NT has a lasting impact during PET scan
-Ways of studying dopamine is more complex and understanding more detailed than with other NT
-Hypothesis on causes of SZ only as good as methods for studying NT
Carlsson et al (1999)
Evaluation A03
Generalisability can be claimed to be low due to the inclusion of animal research within the review. Rodents such as mice used in research into PCP have smaller brains, including a smaller frontal lobe and overall reduced cortex volume compared to humans. Therefore, they are likely to have a different neurotransmitter functioning to humans; so the results collected from studies into the effect of PCP on the brain involving mice cannot be truly reflective of a human brain and the effect of neurochemical imbalances in causing SZ
Carlsson et al (1999)
Evaluation A03
We can question the validity of Carlsson’s conclusions based on the use of secondary data in his review as it suggests an element of subjectivity in the selection of studies. Carlsson’s aim of finding evidence of a further cause of SZ beyond the dopamine hypothesis may have influence his inclusion/omission of studies in the review, implying an element of research bias. Contradictory data may have been left out the review as it didn’t meet the research aims with, meaning we can question the extend of which we can trust Carlsson’s explanation of SZ beyond dopamine and the effect of other neurotransmitters such as glutamate and serotonin.
Carlsson et al (1999)
Evaluation A03
Carlsson utilised triangulation of data, pooling data from 33studies to reach the conclusions suggesting the impact of glutamate and serotonin on SZ as well as dopamine. The multiple supporting evidence from a wide range of studies such as from animal studies and those looking at acute SZ and SZ in remission allowed Carlsson to ensure his findings were credible and high in reliability.
Carlsson et al (1999)
Evaluation A03
This review has good application to society as it advocates further research into the development of drugs to treat SZ, with a focus on avoiding the negative side effects such as Parkinson-like symptoms and considering the role of other neurotransmitters such as glutamate. This could help those previously non responsive to antipsychotic treatments and had little improvement in symptoms; with evidence from the drug clozapine showing promising results in treating treatment resistant patients. The new area of focus could possibly increase the success rate of antipsychotic drugs from 60%.
