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Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies
  1. Department of Medical Sciences, Section of Neurology, Università del Piemonte Orientale A Avogadro, Ospedale Maggiore, Clinica Neurologica, 28100 Novara, Italy cantello{at}
    2. A J LEES
    1. Departments of Clinical Neurology and Neurochemistry, Institute of Neurology, Queen Square, London WC1N 3BG, UK
    1. Dr G Giovannoni g.giovannoni{at}

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    We read with much interest the article by Giovannoniet al 1 depicting the clinical entity that goes under the name of “hedonistic homeostatic dysregulation” in parkinsonian patients.

    Obviously, the scientific background that allowed the authors to disentangle the syndrome includes two basic concepts: (1) exogenous dopaminergic stimulation and its fluctuations can and do affect mood in the parkinsonian patient and (2) the target of this influence is the reward related dopamine system, arising from the ventral tegmental area of the mesencephalon and innervating wide regions of the frontal and temporal lobes. Nowadays, these concepts may seem trivial, but they were certainly not so in the late 1980s, when I coauthored two papers that appeared in thisJournal.2 3 Contrary to Giovannoni et al,1 I do think it fair to remind readers of these articles, because they may help the interested reader to understand more of the long story of Parkinson's disease, dopamine, and depression. In the 1986 paper,2 we provided the first controlled demonstration that a state of dopaminergic hypoactivity (end of dose deterioration) was significantly (p<0.05) associated with a negative mood swing. The control was represented by patients with advanced rheumatoid arthritis whose motor ability fluctuated predictably because of their joint stiffness on awakening. Patients with Parkinson's disease who were steadily depressed (they were depressed even in their mobile periods), were significantly (p<0.05) less prone to a further mood worsening during immobility than patients who did not have a steady depression. We interpreted this as evidence that the dopaminergic system implicated in mood regulation was so severely affected in the former group, to prevent significant fluctuation. But because the motor status of these patients did fluctuate, the system should have been non-nigrostriatal—that is, mesocorticolimbic. These findings, or their essence, were replicated by independent investigators.4 In the second paper,3 we used an amphetamine-like compound—methylphenidate—to test the functionality of the reward or pleasure related dopamine system in patients with Parkinson's disease with major depression, in non-depressed patients with Parkinson's disease, in non-Parkinson's disease patients with major depression, and in age matched healthy controls. The methylphenidate test is used by biological psychiatrists, including studies of people addicted to central stimulants, which relates to the thesis of Giovannoniet al.1 The overall result was that patients with Parkinson's disease with major depression showed characteristically a poor euphoriant response to the intravenous injection of the drug. The pharmacological target of central stimulants is the mesocorticolimbic dopamine system, and particularly the terminals that synapse in the nucleus accumbens, another concept coming back in the paper by Giovannoni et al.1 Hence we suggested that a derangement of this pathway was very likely to have a contributory role in the pathogenesis of depression. Again there was a replication by at least one independent experimenter.5

    Now, in the work by Giovannoni et al,1 this earlier evidence not only is indirectly confirmed, but has gained another, more complex clinical significance. Indeed, the picture that they describe includes, apart from mood disturbances, a series of behavioural abnormalities that are akin to those of addicted people. However, the basic concept remains that, as dopamine is the pleasure transmitter and Parkinson's disease is the dopamine disease, one of the multiple Parkinson's disease facets is a disease of the brain pleasure centres.


    Giovannoni and Lees reply:

    Cantello further highlights the involvement of the dopaminergic system in mood and reward. His earlier work demonstrates that this system is dysfunctional or hyporesponsive in patients with Parkinson's disease who are depressed. In comparison patients with Parkinson's disease with hedonistic homeostatic dysregulation have cyclical dysfunction of the dopaminergic reward system, with periods of hypofunction and hyperfunction. It is well known and widely accepted that patients with Parkinson's disease have a cyclical mood disorder, which mirrors the fluctuations in their motor function. What we wanted to highlight in our article is that in a few patients this cyclical mood disorder provides the substrate for the development of a behavioural disorder not too dissimilar from addiction. We deliberately avoided using the term addiction because of its negative connotations and the difficulty of untangling the motor requirements from the mood elevating effects of dopamine replacement therapies.

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