Paper 2 Clinical: Studies – Carlsson et al (2000)



One study in detail of schizophreniaCarlsson et al (2000) Network interactions in schizophrenia — therapeutic implications-10477590805Before you start:What is schizophrenia?What brain regions are associated with the biological explanations of schizophrenia; can you find them on the illustration?How does neurotransmission work?What do you know about dopamine in general?What do know about the dopamine hypothesis of schizophrenia?What evidence is there for the dopamine hypothesis?What evidence is there against the dopamine hypothesis?What do you know about drug treatments for schizophrenia?What do you know about PET scanning?Design a PET scan experiment to research the role of dopamine in schizophrenia.00Before you start:What is schizophrenia?What brain regions are associated with the biological explanations of schizophrenia; can you find them on the illustration?How does neurotransmission work?What do you know about dopamine in general?What do know about the dopamine hypothesis of schizophrenia?What evidence is there for the dopamine hypothesis?What evidence is there against the dopamine hypothesis?What do you know about drug treatments for schizophrenia?What do you know about PET scanning?Design a PET scan experiment to research the role of dopamine in schizophrenia.339090020320003530600212725This paper includes lots of terminology; look at these words and see whether you can decide on no more than six categories to which they belong; sort the words and find out more about at least two from each category: 00This paper includes lots of terminology; look at these words and see whether you can decide on no more than six categories to which they belong; sort the words and find out more about at least two from each category: 4914900120650dysphoriaanhedoniaSPECTbasal ganglianucleus accumbensstriatumsynergy0dysphoriaanhedoniaSPECTbasal ganglianucleus accumbensstriatumsynergy3629025120650serotoninglutamategabaextrapyramidal dysfunctionamphetaminecatatoniahypofrontality00serotoninglutamategabaextrapyramidal dysfunctionamphetaminecatatoniahypofrontality-69024533782000Carlsson’s (2000) paper provides a review of the current understanding of the ways in which different neurotransmitters interact with each other and how “dramatic synergism between a variety of monoaminergic agonists and MK-801 or other NMDA receptor antagonists” may provide a more advanced neurochemical explanation of schizophrenia.This study does not collect primary data and therefore it is not laid out in the usual APFC format. When you describe the “study” you need to be aware of the background, aims, findings and conclusions. You should also be able to describe how Carlsson would have gone about sourcing his secondary data, i.e. by conducting a literature review, by searching psychological research databases of credible peer-reviewed, published work.In terms of depth, the longest essay you could be asked to write on this study is 20 marks. Depending on the question asked, at most you are likely to have about 10 minutes writing time for the AO1 (description) and 10 minutes for the AO3, (evaluation). The exam might focus on any part of the article/study and the question could be description, application or evaluation based, (or a combination). Evaluation could focus on supporting and refuting research, application and methodological strengths/weaknesses of the studies used in the review (as long as they are explicitly linked to the study and Carlsson et al.’s choice of using those studies).BackgroundCarlsson starts by explaining that …until recently the dopamine hypothesis was only ever supported by “indirect” evidence; now PET imaging has demonstrated that there is abnormal dopaminergic activity in certain brain regions in people with schizophreniaHe goes onto say that…schizophrenia is usually treated by inducing a state of hypodopaminergia, i.e. lowered dopamine levelsthe side effects of reducing dopamine levels are unpleasant, (e.g. extrapyramidal dysfunction, dysphoria and anhedonia) especially in the periods in between acute episodes, where people with schizophrenia may revert to more ‘normal’ levels of dopamine; arguably typical anti-psychotics (i.e. dopamine antagonists) bring the person down to atypically low levels in between psychotic episodeswe urgently need to develop drugs that prevent relapse without these side effectsResearch into dopamine… PET and SPECT scans have been completed using radio-labelled dopa or fluorodopa in order to measure how the brain uses dopamine in areas such as the basal ganglia; drug-na?ve people with schizophrenia compared with age matched controls; they found that when the Pps were given amphetamines, this enhanced release of dopamine significantly more in the SZ group and was more likely to induce SZ symptomsCarlsson notes that a lot of problems exist with the research into the role of dopamine in causing schizophrenic symptoms;some people with schizophrenia show dopamine levels that are within the normal range; dopaminergic dysfunction may only accounts for symptoms in a sub-group of patientssome research suggests that people with ‘catatonic’ symptoms may in fact have hypodopaminergic activityin imaging studies such as the one mentioned above, the stress of the procedure may be another cause of the abnormal levels of dopamine not necessary the same in non-stressful situations the Pps in these studies were in acute episodes, and the situation may be different in people with chronic symptoms Laruelle et al. notes that amphetamine-induced release of dopamine in schizophrenic patients in remission is within the normal range just because radiolabelled dopamine is synthesised more rapidly in Pps with SZ this does mean that endogenous dopamine synthesis is equally abnormal.AimsCarlsson hypothesises that…excess dopamine may be a by-product of dysfunction of some other neurotransmitter; also an excess in one area may be compensating for a deficiency in some other areaHe says to understand schizophrenia we must…examine other neurotransmitters to see whether there are abnormalities in people with schizophrenia, BUT…the trouble is they are not as easy to study in a living brain as dopamine. the easiest to study is SEROTONIN; you can study serotonin levels using a radiolabelled precursor (5-hydroxytryptophan) in order to see how quickly serotonin is synthesised; similar research has been done with people with depression and the expected abnormalities revealed.FindingsThe glutamate hypothesis…PCP or ‘angel dust’ is a street drug and like amphetamines it also induces schizophrenic-like symptomsPCP is a powerful antagonist on the NMDA, glutamate receptor; PCP has the effect of reducing glutamate levels; could hypoglutamatergic activity be a causal factor in schizophrenia? If so is this because glutamate regulates levels of dopamine and/or serotonin?Evidence: studies using SPECT imaging have found that the NMDA antagonist ketamine (effect: reduces glutamate levels) enhances amphetamine-induced dopamine release in humansexperiments with rats have looked at the role of NMDA antagonists and found a slight impact on dopamine release of dopamine, replicated in other laboratories. some NMDA antagonists, however, seem to inhibit dopamine release; suggesting that decreased glutamate may bring about schizophrenic symptoms via some route other than increased dopamine releaseNMDA receptor antagonists appear to stimulate 5-HT (serotonin) turnover and release more consistently than dopaminergic activity, thus high levels of serotonin may also be linked to reduced levels of glutamate.post mortem studies suggest hyperserotonergic function in people with paranoid schizophreniaPCP research seems contradictory, sometimes PCP seems to enhance rather than reduce the release of glutamateCarlsson and Carlsson (1989) gave mice drugs to reduce their motor activity and found that they could induce motor activity again by blocking glutamate receptors in the nucleus accumbens, using a drug called MK-801. This may be seen as a good thing BUT…Systemic treatment with these drugs caused a highly abnormal motor activity, e.g. compulsory forward locomotion with apparently total loss of the ability to switch between different behavioural patterns; systemic treatment will presumably inhibit NMDA receptors not only in the basal ganglia but also, for example, in the cerebral cortex, potentially leading to negative symptoms of schizophrenia; hypofrontality could result from failure of cortical association pathways, dependent upon glutamatergic activity. glutamatergic failure in the cerebral cortex may lead to negative symptoms, whereas glutamatergic failure in the basal ganglia could be responsible for the positive symptoms. 386715039370Figure 1: How does glutamate regulate dopamine; the brake and the acceleratorThe descending glutamatergic pathway acts as an accelerator on the meso-cortical dopamine pathway ultimately guiding higher brain centres in the cortexif NMDA receptors in the midbrain are dysfunctional, dopamine misfiring may contribute to cognitive impairments and symptoms of schizophreniain contrast glutamate neurons that connect to dopamine neurons involved in the limbic system have a GABA interneuron inbetween, GABA inhibit the release of dopamine, acting as a brake on dopamine pathways, if this brake is removed by for example less glutamatergic activity excess dopamine can contribute to the experience of positive symptoms of psychosiswatch?v=jivjfvMYi-Y00Figure 1: How does glutamate regulate dopamine; the brake and the acceleratorThe descending glutamatergic pathway acts as an accelerator on the meso-cortical dopamine pathway ultimately guiding higher brain centres in the cortexif NMDA receptors in the midbrain are dysfunctional, dopamine misfiring may contribute to cognitive impairments and symptoms of schizophreniain contrast glutamate neurons that connect to dopamine neurons involved in the limbic system have a GABA interneuron inbetween, GABA inhibit the release of dopamine, acting as a brake on dopamine pathways, if this brake is removed by for example less glutamatergic activity excess dopamine can contribute to the experience of positive symptoms of psychosiswatch?v=jivjfvMYi-YOverall, it appears that…Schizophrenic symptoms may depend, among other things, upon an interplay between dopamine and glutamate pathways leading to the striatum from the lower brainstem and cortex, respectively.Glutamate can control dopamine in two ways, serving as either a ‘brake’ or an ‘accelerator’; see figure 1Carlsson finally comments on how this knowledge can help with treatment options: Haloperidol blocks D2 dopamine receptors sites and was more effective than M100907 (a selective 5HT antagonist) in reducing amphetamine-induced hyperactivity however the reverse was true of MK-801 (NMDA antagonist –lowers glutamate) induced hyperactivityNot clear whether M100907 (serotonin antagonist) can be used as an antipsychotic; it may be that it works for some patients more than others possibly due to different causes of their symptomsusing both types of drug together may also be more effective than either on its own, e.g. clozapine and other ‘atypical’ antipsychotics are both anti-dopaminergic and anti-serotonergicclozapine is often effective for treatment resistant schizophrenics for whom decreasing dopamine levels has not worked, this may be because their symptoms are being caused by low glutamate levels which are in turn affecting serotonin levels.drugs that affect glutamate levels, e. g are potentially an exciting advancement for people with schizophrenia who have not experienced relief from other medications, e.g. glutamate agonists (AJW says, for more information see: Seeman and Guan, 2009)other new drugs are being worked on which stabilize dopamine levels without inducing the hypodopaminergiaConclusionsIn conclusion, Carlsson suggests that…a number of subpopulations with different pathogenesis may exist among schizophrenic patientsa mechanism involving a glutamatergic deficiency appears to deserve special attention. this deficiency may well be secondary to, for example, a failure of connectivity arising at an early developmental stagea glutamatergic deficiency linked to..the meso-cortical pathways could be responsible for a variety of cognitive and negative symptomsin subcortical, meso-limbic pathways could lead to elevated dopamine levels, potentially triggering a compensatory reduction of presynaptic dopaminergic activityevidence of elevated serotonergic activity, probably located both pre- and post-synaptically probably contributes significantly to the positive, and presumably also to the negative symptomatologyfurther research needs to be conducted into the development of the disease over time, for example explaining why psychotic episodes appear to lead to further deteriorationfurthermore, other neurotransmitters, such as acetylcholine, gaba and neuropeptides, should also be explored as potentially involved in triggering schizophrenic symptomsEvaluation of Carlsson et al (2000)Research EvidenceEvidence that supports Methodological strengths and weaknesses of this researchEvidence that refutes Methodological strengths and weaknesses of this researchApplications to real lifeCommentary on the suggestions for application to real lifeAlternative explanations of schizophrenia, e.g. other biological explanation and psychological accounts that look at social factors for mentary on these alternative explanations of schizophrenia ................
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