The dopaminergic basis of negative symptoms in schizophrenia: an addendum

We would like to address the results of two recent positron emission tomography (PET) imaging studies and discuss them in relation to our own findings [1]. The first study we would like to refer to is an [¹⁸F]FDOPA PET investigation performed in two independent cohorts of drug-free patients with schizophrenia [2]. [¹⁸F]FDOPA is a direct precursor of dopamine, and its uptake is generally assumed to reflect presynaptic dopamine synthesis and storage capacity. In contrast to earlier [¹⁸F]FDOPA PET studies, Eisenberg et al. failed to find elevated [¹⁸F]FDOPA uptake in patients with schizophrenia. However, the study observed inverse correlations between [¹⁸F]FDOPA uptake rates into the putamen and severity of negative symptoms in both cohorts. Thus, the Eisenberg et al. findings indicate that reduced dopamine transmission in the putamen may be an important element in the formation of negative symptoms of schizophrenia.

The second study we would like to address [3] presents the results of a PET study on the effects of oral methylphenidate (MPH) administration on non-displaceable binding potential (BP_ND) values of the dopamine D_2/3 receptor agonist radioligand [¹¹C]-(+)-PHNO in individuals at clinical high-risk (CHR) for psychosis. Changes in radioligand binding to dopamine D_2/3 receptors after a pharmacological or behavioral challenge provide an indirect measure for the fluctuations in extracellular dopamine levels. The authors aimed to replicate and extend findings on alterations in subcortical availability of dopamine in CHR individuals, as previous studies have shown that subcortical dopamine functioning is elevated in full-blown psychosis, and that enhanced dopamine transmission might be present even before psychosis onset [4, 5]. This, however, was questioned by a more recent meta-analysis [6]. The main finding of the study by Girgis et al. [3] was that, compared to non-CHR controls, CHR subjects showed greater changes in [¹¹C]-(+)-PHNO BP_ND values (∆BP_ND) in response to the MPH challenge. This conforms well with results from earlier challenge-studies in patients with schizophrenia [1, 4, 7,8,9,10,11] and extends the use of this method towards prodromal stages of psychosis (which, of course, can only be termed as such in retrospect). In addition, the study by Girgis et al. observed an inverse relationship between the expression of negative symptoms and [¹¹C]-(+)-PHNO ∆BP_ND in the ventral striatum of CHR subjects.