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Presynaptic Dopaminergic Function: Implications for Understanding Treatment Response in Psychosis

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Abstract

All current antipsychotic drugs block dopamine (DA) receptors, but the nature of the DA dysfunction in schizophrenia has not been clear. However, consistent evidence now shows that presynaptic dopaminergic function is altered in schizophrenia, specifically in terms of increased DA synthesis capacity, baseline synaptic DA levels, and DA release. Furthermore, presynaptic dopaminergic function is already elevated in prodromal patients who later developed the disorder. Currently available antipsychotics act on postsynaptic receptors, not targeting presynaptic DA abnormalities. This has implications for understanding response and developing new treatments. The lack of normalization of the abnormal presynaptic function could explain why discontinuation is likely to lead to relapse, because the major dopaminergic function persists, meaning that once treatment stops there is nothing to oppose the dysregulated dopamine function reinstating symptoms. Furthermore, it suggests that drugs that target presynaptic dopaminergic function may constitute new treatment possibilities for schizophrenic patients, in particular, for those in whom antipsychotics are poorly effective. In addition, the longitudinal changes with the onset of psychosis indicate the potential to target a defined dynamic neurochemical abnormality to prevent the onset of psychosis.

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Conflicts of interest

This study was funded by a Medical Research Council (UK) grant to Dr. Howes (grant number: MC-A656-5QD30), the Wellcome Trust, and the National Institute of Health Research Biomedical Research Council grant to King’s College London. Dr. Howes has received investigator-led funding or been on the speaker bureau of AstraZeneca, BMS, Eli Lilly, Jannsen, Leyden-Delta, Roche and Servier. Dr. Bonoldi has no conflict of interest.

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  1. Department of Psychosis Studies, Institute of Psychiatry, King’s College of London, De Crespigny Park 16, London, SE5 8AF, UK

    I. Bonoldi & O. D. Howes

  2. Psychiatric Imaging Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, W12 0NN, UK

    I. Bonoldi & O. D. Howes

  3. Section of Psychiatry, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy

    I. Bonoldi

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Bonoldi, I., Howes, O.D. Presynaptic Dopaminergic Function: Implications for Understanding Treatment Response in Psychosis. CNS Drugs 28, 649–663 (2014). https://doi.org/10.1007/s40263-014-0177-z

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