Dopaminergic function in depressed patients with affective flattening or with impulsivity: [18F]Fluoro-l-dopa positron emission tomography study with voxel-based analysis

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Abstract

A decreased striatal presynaptic dopaminergic function has been reported in depressed patients with affective flattening and psychomotor retardation, using 18F-fluorodopa positron emission tomography and regions-of-interest. The present study aimed to investigate regional `[18F]dopa uptake in mesolimbic and mesocortical dopaminergic projections with the hypothesis that there should be a decrease in mesolimbic [18F]dopa uptake associated with affective flattening and psychomotor retardation. [18F]Dopa-positron emission tomography and anatomical magnetic resonance imaging datasets from 12 screened depressed patients with either marked affective flattening and psychomotor retardation (n = 6) or with marked impulsivity (n = 6), and from eight healthy subjects, were analyzed using a voxel-based approach. Regional differences in [18F]dopa uptake rate constant (Ki) values between the healthy group and the two depression subgroups were compared using both statistical parametric mapping and cluster-based regions-of-interest. Patients with affective flattening and psychomotor retardation had [18F]dopa Ki decreases in the left caudate, bilateral putamen and nucleus accumbens, left parahippocampus and dorsal brainstem. Impulsive depressives had [18F]dopa Ki decreases in the anterior cingulate and hypothalamus, and an increase in the right parahippocampal gyrus. These findings support distinct regional dysfunctions of monoamines depending on the depressive symptomatology.

Introduction

The clinical picture of depression involves depressed mood, somatic complaints and symptoms, anxiety symptoms with sometimes increased irritability, psychomotor agitation or retardation, and a dimension involving affective flattening and loss of interest or pleasure (DSM-IV-R, 1996). It has been suggested that within the depressive syndrome, those diverse symptoms may have distinct neurophysiological correlates, such as the association between decreased dopamine turnover and psychomotor retardation (Sobin and Sackeim, 1997, Drevets et al., 1999). Indeed, affective flattening, along with psychomotor retardation, may arise from disruption of reward-seeking behaviors, motivation and environmental responsivity, with neuronal substrates that involve central dopamine-containing systems (Swerdlow and Koob, 1987). Hence, reduced dopaminergic transmission might contribute to specific behavioral symptoms of depression.

To find links between a neurotransmission system, such as the dopaminergic one, and depression symptoms, the depressive syndrome may be dissected into meaningful symptomatic clusters, such as those proposed by Pierson et al. (1996), who reported that two depressive sub-types, so-called “retarded” and “impulsive” depression, had different event-related potential patterns. The “retarded” depression sub-type was defined as a depression picture with marked psychomotor slowing and affective flattening, including symptoms that have been hypothesized to be related to dopamine hypotransmission such as lack of emotional involvement, subjective indifference to pleasant events and unpleasant events, subjective indifference to sensorial stimuli and observed loss of pleasure seeking. The “impulsive” sub-type, on the other hand, was defined as depression with prominent irritable mood, including subjective irritability, observed and subjective explosive mood (angry outbursts), subjective and objective unstable affect, and increased emotionality according to the Depressive Mood Scale (Jouvent et al., 1988).

Contrasting such clinically “impulsive” depressives with depressives with affective flattening and psychomotor retardation, we performed a positron emission tomography (PET) study using [18F]dopa and regions-of-interest (ROIs) in the striatum, and reported that only depressed patients with affective flattening and psychomotor retardation had a decreased presynaptic striatal dopamine function in the left caudate, when compared with “impulsive” depressed patients and with healthy subjects (Paillère-Martinot et al., 2001).

However, the nigrostriatal dopaminergic pathway is only a part of the central dopamine (DA)-containing systems, which includes the mesolimbic, tuberoinfundibular and mesocortical pathways. Notably, structures in both nigrostriatal and mesocorticolimbic dopaminergic pathways, such as the anterior cingulate, the amygdala–hippocampal complex and the ventral striatum, are implicated in emotional and reward-related behaviors (Watanabe and Kimura, 1998, Chau et al., 2004). Also, decreased mesolimbic DA function has been hypothesized in the depressed phase of bipolar disorder (Drevets, 2001). Thus, in the present study, striatal and extra-striatal DA projections were investigated in the whole brain volume, with the hypothesis that [18F]dopa uptake should be decreased in the mesolimbic dopamine pathways of depressed patients with psychomotor retardation and affective flattening. The SPM voxel-based method was used to further investigate the [18F]dopa PET scans that were performed in the patients of our previous study. In addition, [18F]dopa uptake Ki values were determined using a region-of-interest approach in the regions detected by the voxel-based method.

Section snippets

Subjects

The patients were 12 right-handed inpatients with a DSM-IV diagnosis of major depressive episode (MDE) enrolled from consecutive admissions over a 2-year period. Diagnoses were established on the basis of clinical interviews and administration of the Mini-International Neuropsychiatric Interview (Sheehan et al., 1998), which is a short structured diagnostic interview for DSM-IV criteria. Inclusion criteria involved high depression scores (> 25 on the Montgomery-Åsberg Depression Rating Scale,

Between-group comparisons

Relative to healthy subjects, patients with affective flattening and psychomotor retardation had significant reductions in [18F]dopa uptake Ki values in the left caudate (Fig. 1A) and posterior putamen, and in the right posterior putamen. [18F]Dopa uptake Kis in patients with affective flattening were decreased bilaterally in accumbens nuclei (Fig. 1A) and in the left parahippocampus. Also, decreases in [18F]dopa uptake Ki were detected within the brainstem, in a region corresponding to the

Discussion

This study aimed at investigating the regional pattern of [18F]dopa uptake in clinically contrasted subgroups of depressive patients, namely depressives with affective flattening and depressives with irritable mood, so-called impulsive depressives, using a voxel-based analysis of 3D-[18F]dopa-PET images. The patients with affective flattening displayed decreased [18F]dopa Ki in left caudate, bilateral putamen and accumbens nuclei, left parahippocampus and dorsal pons, with an increased [18

Acknowledgments

The authors thank Pr. André Syrota from the Atomic Energy Commission (CEA) for his support, F. Dollé and the cyclotron staff, R. Rougetet and F. Napoleone for technical support, and P. Hantraye for thoughtful comments, at Service Hospitalier Frédéric Joliot, Orsay. V.B. was supported by a doctoral fellowship from Sanofi-Synthelabo, the Atomic Energy Commission and the Région Ile-de-France.

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