Let’s Revise: Edexcel A Level (AJW) One contemporary study of schizophrenia: Carlsson et al (2000)

Aim To provide an up-to-date review of the current status of the dopamine hypothesis To raise awareness of the potential role of other neurotransmitters, e.g. glutamate, serotonin and GABA To present suggestions for future drug treatments for the wide range of people with schizophrenia, many of whom are “treatment resistant” or who live with the extreme side effects (e.g. extra-pyramidal dysfunction)

What does Carlsson say about the function of neurotransmitters in relation to schizophrenia? excess dopamine may be a by-product of dysfunction of another neurotransmitter excess in one area of the brain may be a way of compensating for a deficiency in another brain area

Why does Carlsson think hyperdopaminergia is only part of the answer? some people with schizophrenia show dopamine levels within the normal range dopaminergic dysfunction may only accounts for symptoms in a sub-group of patients some people with ‘catatonic’ symptoms have hypodopaminergic activity

What does he say about other neurotransmitters? dopamine levels may be controlled by serotonin levels, if serotonin levels are too high, this could be linked to increased dopamine levels low levels of glutamate, may allow both serotonin and dopamine levels to become too high glutamatergic failure in … the cerebral cortex may lead to negative symptoms the basal ganglia could be responsible for the positive symptoms  

Glutamate as a dopamine “accelerator” In the meso-cortical pathway glutamate acts as an accelerator leading to increased dopamine activity if this goes wrong… and glutamate levels fall too low dopamine levels drop leading to negative symptoms    

Glutamate as a dopamine “brake” in the meso-limbic pathways… glutamate acts as a brake signalling to GABA neurons to inhibit dopamine production if the brake does not work glutamate levels are too low leading to low levels of GABA thus high levels of dopamine resulting in positive symptoms

serotonin antagonists to bring down serotonin levels What does Carlsson say regarding future drug treatments for schizophrenia? serotonin antagonists to bring down serotonin levels glutamate agonists - to increase glutamate levels differing symptoms may be the result of differing neurochemical aetiologies requiring differing treatments

Evaluating Carlsson et al (2000) Studies of PCP: Angel Dust (this drug reduces glutamate) One strength of Carlsson’s theory that dopamine levels may be elevated due to low levels of glutamate is that it is supported by experiments with the drug PCP or ‘angel dust’. These studies demonstrate that PCP, an antagonist on the NMDA, glutamate receptor can induce schizophrenic-like symptoms. This is important because it shows that PCP (a drug which decreases glutamate levels) has very similar effects to drugs such as amphetamine which increase dopamine levels, suggesting that schizophrenia may be linked to hypoglutamatergic activity. (well-developed chain of reason)

Competing argument This said, some psychologists argue that PCP research is contradictory and sometimes PCP actually enhances rather than reduces the release of glutamate this ambiguity casts doubt on hypoglutamatergia as a cause of schizophrenia.

Studies with ketamine (this drug also reduces glutamate ) A further strength is that SPECT imaging studies show that another glutamate antagonist, ketamine, enhances amphetamine-induced dopamine release in humans. These findings have also been replicated with rats under more controlled conditions demonstrating that the conclusions regarding the role of glutamate in increasing dopamine levels are both reliable and internally valid.

Competing argument Animal research criticism evolutionary continuity Role of environmental and cultural factors is overlooked EBH, Luhrmann The part to be played by psychological therapies that do not use drugs and lock people into a life of fluctuating dopamine levels, Murray’s comments about his career

Applications to treatment: clozapine Post mortem studies Suggest hyperserotonergic function in people with paranoid schizophrenia Applications to treatment: clozapine Les tardive dyskinesia so more ethical and likely greater compliance

Carlsson and Carlsson (1989) A final strength of Carlsson’s theory, regarding the role of glutamate in schizophrenia, is that his ideas are supported by his experiments with mice Mice are given drugs to reduce motor activity Their motor activity can be restarted by blocking glutamate receptors with the drug MK801 Thus reducing glutamate and increasing serotonin and dopamine in the nucleus accumbens He also observed however, that if you keep on giving the mice MK801 (sustained low levels of glutamate) you get highly abnormal behaviour (similar to psychotic behaviour) This is important as it suggests that anything that interferes with glutamate may be a causal factor in schizophrenia and his also offers another possible treatment regarding glutamate agonists.

Mounting strengths but what about the weaknesses? Animal experiments Post Mortem studies Brain imaging What weaknesses can you think of, now make these weaknesses specific to our understanding of the role of glutamate and our understanding of schizophrenia?

Factors that are overlooked by Carlsson? The papers focuses on biochemisty without considering environmental factors which could impact levels of different neurotransmitters Could diet, lifestyle, sleep, stress impact glutamate and therefore be implicated in the treatment rather than looking to new classes of drugs which may also have their own debilitating side effects?

The nuanced killer conclusion think about … Harry and Kate in Angel Baby Nathanial in the Soloist their friends and family members Brian, the homeless man in London living a desperate life on the streets of London Does this give you some perspective? How do you feel about Carlsson’s contribution The conclusion should not be overly emotional dissect the issues and what we have learnt appeals to the human angle and socio-cultural, political and economic factors which drive research and publication bias Think about Murray?