SZ and NT and Carlson 2000

Question 1

Carlsson et al [2000] contemp

Aims

Answer 1

• To review studies on the relationship between neurotransmitter levels
– especially dopamine and glutamate,
– on the symptoms of schizophrenia.

• To explore a rival theory, that glutamatergic deficiency or hypoglutamatergia (too little of a neurotransmitter called glutamate).

• consider the need for further research into drug treatments that target neurotransmitters other than dopamine
– and improve drug treatments by reducing relapse rates as well as side effects

Question 2

Carlsson et al [2000] contemp

method / procedure

Lit Review

Answer 2

• Carlsson uses Secondary data

• Lit Review (on research and the current theory)

• Studies investigated Neurochemical lvls of parients
– and studies into drugs that induse psychosis symptoms
(e.g. Amphetamine (up dope) or PCP thats also linked to Psychosis)

– used brain scans e.g PET to research Dope lvls

– Research into the effectivness and Function of Drugs used to treat SZ
– esspecialy ones supporting alt NT hypotheses

– used range of Brain scans, Animal studies, post mortems and human ppt research in the Review

Example of reseach used in Lit study:

Miller and Abercrombie (1996)

– used animals, super imposed NMDA antagonist (to block Glute receptors) on Amphetamine
– gave to animals
– led to increased release of Dope

Question 3

Carlsson et al [2000] contemp

Section 1 Results

Dopamine as an Explenation of SZ (too simplistic) ☆☆

Answer 3

• Carlsson explains evidence from PET/SPECT that supports the Dopamine Hypothesis (dopaminergic dysfunction)

– Schizophrenic participants show more dopamine activity than a healthy control group, especially in a part of the brain called the basal ganglia.

– However, Laruelle et al. (1999)
found that schizophrenia patients in remission (not showing symptoms) only had normal dopamine activity

– Carlsson et al.
points out the patients taking antipsychotics complain most about the side-effects while their symptoms are in remission

– not surprising if their dopamine activity becomes normal during this time and the drugs are causing hypodopaminergia (too little dopamine)

– This all suggests that Dopamine alone is too simplistic as an Explenation of SZ

Question 4

Carlsson et al [2000] contemp

Section 2 results: Beyod dopamine

Glutamate is a Promising Alt Cause

Answer 4

NT interact and affect one another

– so Dopeamine cant be the onky NT that causes SZ symptoms

• Carlsson et al 2000
– focuses of Glutamate cuz:
– Drugs like PCP produce psychotic symptoms BUT Dope isnt Activated by it, It does however Stimulate the NMDA glutamate receptor

• Lodge et al 1989 claimed Glutamate activity at the NMDA receptors causes Psychotic Reactions in Rats and People

Question 5

Carlsson et al [2000] contemp

Section 3 results
Glutamate as an Explenation of SZ
☆☆☆

Answer 5

High Glute = low dope (Break)

Low Glute = High dope (Accelerator)

PCP = Psychotic ^=Glute ø=Dope
So High Glute inhibits Dope

PCP more likley to Result in Psychosis than Amphetamine

Miller and Ambercrombie 1996
– shows Dope increased if Glute decreased (Shown by block NMDA receptors)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

• There is a lot of research evidence supporting the role of low levels of glutamate in the development of psychotic symptoms

– Gaba + Glutamate seems to regulate the behaviour of dopamine and sheds some light on the behaviour of dopamine in the brain

• Carlsson describes how it acts as an accelerator” (increasing dopamine activity)
– or a “brake (decreasing it).

• The psychotic side-effects of PCP are reduced by a chemical called
– LY354740
– which increases the activity of glutamate but doesn’t do anything directly to dopamine
– (this suggests that high glutamate activity has the effect of inhibiting dopamine).

• The use of PCP is more likely to result in psychosis even more so than research has suggested in amphetamine users

• Miller & Abercrombie (1996)
– show that the release of dopamine is increased if glutamate activity is reduced
– (by blocking the NMDA receptors which glutamate binds with)
– this means that the drug inhibits the action of glutamate
– reducing its actions in areas of the brain

Question 6

Carlsson et al [2000] contemp

Section 4 Results ☆☆☆

Answer 6

• Some research has found a relationship between glutamate levels and dopamine production

– reduced levels of glutamate are associated with increased dopamine release

• Glutamate failure in the cerebral cortex may lead to negative symptoms

• whereas glutamatergic failure in the basal ganglia (Striatum) could be responsible for positive symptoms.

Question 7

Carlsson et al [2000] contemp

Section 5 Results ig ☆

Answer 7

• Carlsson proposes that the thalamus “filters off” neurortransmitters coming out of the stratium (in Basal Ganglia)
– to stop the cerebral cortex from overloading.

• There are two “pathways” through the thalamus:

• In the indirect pathway:
–n too much dopamine (hyperdopaminergia)
– or too little glutamate (hypoglutamatergia)
– reduces the “protective influence” of the thalamus
– this links to positive symptoms

• direct pathway
• which has the opposite effect;

– abnormal dopamine and glutamate activity here will “excite” the thalamus
– starving the cerebral cortex of stimulation
- this links to negative symptoms

Question 8

Carlsson et al [2000] contemp

Section 6 + 7

Drug Treatments ☆☆☆☆☆

Answer 8

Some Patients Respomd better to Antidopaminergic drugs
while some “treatment ressistant” patients may respond better to Glutamatgeric Drugs as their condition may be more Hypoglutamatergia

Carlsson is developing Drugs that Reduce Dope w/o low dope Side effects
– by acting in pre synapse where dope produced not innpost where receptors are
– stops over production of dope, so Brain never Dealnwith abnormal levels so no side effects

(6)

two models (explanations) for schizophrenia:

• hyperdopaminergia (too much dopamine)

• hypoglutamatergia (too little glutamate).

– Some patients respond better to some drugs than others

– might be because some people’s schizophrenia is more dopaminergic and other people’s symptoms are more glutamatergic

• The “treatment resistant” patients who don’t respond to typical antipsychotics (that reduce dopamine)
– might have a more glutamatergic condition instead

(6.5)

Clozapine is an atypical antipsychotic that has better results with “treatment resistant” patients

– with few reported negative side effects, it has been shown to have both antidopaminergic and antiserotonergic functions
– (it reduces dopamine and serotonin levels in the brain)

– it is also highly effective in patients that have previously not responded to treatment

– may be cuz they belong to a subgroup whose disorder may be better explained by hypoglutamatergia (reduced levels of glutamate)

(7)

Carlsson thinks there’s still a future in dopamine research. as well as Glutamate

• Carlsson et al. are researching new drugs which regulate dopamine activity
– without producing harmful hypodopaminergia
– (which creates the unpleasant side-effects of antipsychotics)

• These work by acting at the pre-synapse
– (where dopamine is produced)

– rather than the post-synapse
(where the dopamine receptors are),

– so they stop the brain producing too much dopamine without interfering with the brain’s ability to process dopamine normally

• These drugs are “now in clinical trials” (and that was two decades ago!)

Question 9

Carlsson et al [2000] contemp

con + imp

Answer 9

• The study concludes that further research is needed in developing drugs used to treat schizophrenia that avoid negative side effects

• possibly by considering the role of other neurotransmitters in the development of the disorder

• or regulate production of dope in pre-synapse

• There are drugs under research that reduce dopamine levels without risking the very low levels associated with negative side effects such as Tremors. (Pre-synaptic ones from earlyer)

• The study suggests that schizophrenia may have different types (subpopulations) that could be caused by abnormal levels of different neurotransmitters and not just dopamine

• Ths would have serious implications for the future treatment developments for schizophrenic

• Lack of glutamate might cause patients to have an exaggerated response to dopamine at the post-synapse

• in other words, even though only normal levels of dopamine are being produced, the dopamine receptors can have an extreme reaction

Question 10

Carlsson et al [2000] contemp

cerebal cortex

Answer 10

The cerebral cortex is a area of the brain that is responsible for the frontal, temporal, parietal and occipital lobes

and conssiousness alltogether

low Glute activity in NMDA receptors here (Glutamate failure)
causes - symptoms

Question 11

Carlsson et al [2000] contemp

Basal Ganglia and Striatum

Answer 11

Basal Ganglia controls motor controls, Motor behaviour and motor learning

It contains the Striatum
the brains reward center

Glutamatergic failure here results in Positive Symptoms

Question 12

Carlsson et al [2000] contemp

Gen + Studies representitve of the field at time

Answer 12

Representive sample of studies were used

(studies represented the field of study)

• 33 studies, 14Carlsson took part in
– all on the main type of SZ
– Carlsson is regarded as the foremost researcher in dopamine and SZ

– Sample of Studys is very rep of whats going on in SZ field at the time

– So results are Very Generalisable

Question 13

Carlsson et al [2000] contemp

Gen - from 2000 not gen to today

Answer 13

• took place in the 2000s

• may be time locked as research has moved on since then

• and therefore the studies used in the literature review are no longer representative of what is going on in the schizophrenic field of research today

• meaning it is no longer generalizable

Question 14

Carlsson et al [2000] contemp

gen - animals not gen

Answer 14

• some research you used in the literature review used animals

• such as lodge in 1984 who used Rats and humans
– but rats are not generalizable to the human population
– due to brain differences and reactions to medical stimuli

• and therefore that’s the would not be generalizable for representative of humans with schizophrenia

Question 15

Carlsson et al [2000] contemp

reliability + lab standardised scans

Answer 15

The study is reliable

as it uses lab experience in the literature review by Carlsson who sites only lab experiments

Most of these use modern PET or SPECT brain scan techniques which are standardized Brain scanning Techniques (involving Radioacibe tracers to demonstrate high and low activity in the brain, in the case for dope and Glute)

and therefore replicable

as they are replicable these studies high in reliability

Question 16

Carlsson et al [2000] contemp

rel - unpublished studies at the time

Answer 16

Laurelle et al

Was unpublished at the time at which Carlsson sites it and therefore have not been peer-reviewed

and therefore it may have low inter rater reliability

As peer-reviewed studies are reliable as they’ve been checked by experts for consistencies within the Field of study before publishment

and as it has not been peer-reviewed it could not be deemed consistent within the Field of study by over researchers and whether or not they agree with the interpretation of the data

Therefore overall making this study in carlsson’s literature review unreliable and as a consequence so is carldson’s literature review

Question 17

Carlsson et al [2000] contemp

app

Answer 17

This literature review has led to development of new anti-psychotic drugs

which are improved dopamineergic drugs with fewer side effects based on better and understanding of dopamine pathways

these new atypical drugs affect other neurotransmitters such as glutamate and serotonin

these drugs will be effective that reducing both positive and negative psychotic symptoms with less side effects

and it will be incredibly efficient at treating all types of schizophrenia due to tackling different neurotransmitters

Some of these drugs may tackle the issue at the pre-Synapse where dopamine is formed so there is never an irregular amount of dopamine present and therefore no symptoms/ side effects can develop and the brain never beleives anything is abnormal

This shows how this literature review AIDS be development of the treatment of schizophrenia

Question 18

Carlsson et al [2000] contemp

val - challenges dope hypothesis val

Answer 18

Carlsson questions the dopamine hypothesis validity

he created the original hypothesis in the 1960s

but evidence that second generation anti-sychotics such as clozapine m which blocks serotonin and glutamate receptors as well as dopamine

also seemed to reduce negative symptoms of schizophrenia

so he considers the possible glutamate hypothesis as a cause of schizophrenia

this in itself challenges the validity of the original dopamine hypothesis as well as the revised version

The idea that the glutamate hypothesis is valid and the dopamine hypothesis isnt valid is in itself invalid as it is reductionist

• scientists themselves believe that it may be a combination of both factors and not just one neurotransmitter hypothesis that causes SZ

Question 19

Carlsson et al [2000] contemp

+ Val carlsson also Agrues both hypoth may be true

Answer 19

Despite arguing the glutamate hypothesis is true

he also suggests that both hypotheses may be true

as both should be researched further

scientists also agree with this and believe that both should be considered rather than simply one or the other

therefore this interpretation of Carson’s view on schizophrenia is more valid

than the interpretation in which he believes the glutamate hypothesis is more valid than the dopamine one

Question 20

Carlsson et al [2000] contemp

val + 2ndry data

Answer 20

Carlsson’s literature review due to secondary data which include lots of information from other studies to be reviewed and analyzed

This creates a more complex picture of the Field of research and therefore a more valid conclusion

Question 21

Carlsson et al [2000] contemp

good ethics

Answer 21

Carlson’s literature review has good ethics

and this is because due to it being a literature review there is no participants that are directly affected by the review itself and

therefore there can be no ethical issues directly connected to it

meaning that Carlsson et al 2000 is highly ethical

Question 22

Carlsson et al [2000] contemp

Selection Bias - val

Answer 22

Carlsson himself suggested that the studies reviewed in his literature review

were all mainly studies that were investigating and supporting the possibility of an alternative hypothesis for the cause of schizophrenia

from alternative neurotransmitters other than dopamine mainly of glutamate

This means that the literature review isn’t an accurate view of the area of research into schizophrenia

as evidence that suggested that glutenant may not have an effect on schizophrenia

or other neurotransmitters such as gaba who is not featured as promenently in the literature review as the other neurotransmitters, maybe responsible for the cause of schizophrenia also

By not including some of these studies in the literature review it is therefore an invalid view of the research of schizophrenia and alternative hypotheses