The complexity of using D2-dopamine antagonists in the treatment of patients with schizophrenia

• Schizophrenia is a complex disorder and the view that schizophrenia is caused by hyperdopaminergic activity is an oversimplification. In fact, there are clinical evidence in accordance with a hypodopaminergic condition. Thus, untreated patients show motor disturbances in line with a decreased dopamine activity in the extrapyramidal system, likewise cognitive deficits and negative symptoms. In our research we have explored the evidence of schizophrenia as a hyper- or hypodopaminergic condition. With Positron Emission Tomography (PET) we have not seen any evidence of increased D2-dopamine receptors in the brain of never medicated patients. The major dopamine metabolite homovanillic acid (HVA) was lowered in CSF in line with a decreased dopamine turnover in the brain. Tyrosine is precursor to the synthesis of dopamine and for that aim we have made transport studies in an in vitro model with fibroblasts to determine tyrosine kinetics. The results demonstrated that tyrosine transport is lower in patients with schizophrenia in comparison to healthy controls. Tyrosine kinetics measured with PET demonstrated dysregulation of tyrosine transport into the brain.We have found evidence of schizophrenia as a hypodopaminergic condition. This fact is a problem realizing that our antipsychotics are D2-dopamine antagonists, thus decreasing dopamine activity even further.The concept of schizophrenia as both a hypo- and hyperdopaminergic condition may explain why clozapine, a week D2-antagonist, works more efficiently than other antipsychotic compounds. It should be recognized that positive symptoms are, at least partly, related to changes in dopamine activity and therefore respond very efficiently to D2-dopamine antagonists.

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Biomedicin

Biomedicine

Psychiatry

Psykiatri

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