Psychiatry and Clinical Neurosciences 2008; 62: 345–348
doi:10.1111/j.1440-1819.2008.01814.x
Short Communication
Temporal cortex dopamine D2/3 receptor binding in major depression Soili M. Lehto, MD,1* Jyrki Kuikka, PhD,2 Tommi Tolmunen, MD, PhD,1 Jukka Hintikka, MD, PhD,1,3 Heimo Viinamäki, MD, PhD,1 Ritva Vanninen, MD, PhD,4 Kaisa Haatainen, PhD,1 Heli Koivumaa-Honkanen, MD, PhD,1 Kirsi Honkalampi, PhD1 and Jari Tiihonen, MD, PhD5 1
Department of Psychiatry, 2Department of Clinical Physiology and Nuclear Medicine, 4Department of Clinical Radiology, Kuopio University Hospital, 5Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, Kuopio, and 3 Department of Psychiatry, Paijat-Hame Central Hospital, Lahti, Finland
The aim of this study was to assess the dopamine function of the temporal cortex in major depressive disorder using [123I]epidepride to image D2/3 receptor binding sites. Ten major depressives and 10 healthy controls were selected from a general population sample for single-photon emission computed tomography imaging. Among the major depressives there was a strong bilateral correlation between the scores
OME,1,2 BUT NOT all3 studies have reported higher radiotracer binding in striatal dopamine (DA) D2 receptors in patients with major depressive disorder (MDD). Previous single-photon emission computed tomography (SPECT) studies on DA D2/3 receptors in MDD have utilized [123I]iodobenzamide.1–3 However, its low affinity has mainly limited the studies to the striatal regions, while [123I]epidepride, a high-affinity extrastriatal ligand,4 provides the advantage of recording DA D2/3 receptors in extrastriatal areas with lower receptor densities. We performed this exploratory study of DA function in depression using [123I]epidepride to image temporal cortex D2/3 receptor binding sites in participants with MDD and controls.
S
*Correspondence: Soili M. Lehto, MD, Department of Psychiatry, Kuopio University Hospital, 70210 Kuopio, Finland. Email:
[email protected] Received 26 March 2007; revised 25 October 2007; accepted 3 December 2007.
on the 21-item Hamilton Depression Rating Scale and D2/3 receptor binding. Dopaminergic abnormalities may be present in the temporal cortices of major depressives. Key words: [123I]epidepride, depression, dopamine, single-photon emission computed tomography, temporal cortex.
METHODS The study setting is presented in Fig. 1. None of the participants had ever used antipsychotic medication. There were no comorbid diagnoses in the MDD group. The depressed were not allowed to use antidepressants during the 6 months prior or benzodiazepines during the 3 months prior, and the controls were free of all psychotropic medication. The participants were righthanded, except for one who reported using both hands. All provided written informed consent. The study design was approved by the Research Ethics Committee of Kuopio University Hospital. Both groups were assessed using the structured clinical interview for DSM-IV (SCID-I5). The severity of depression was assessed by a trained researcher using the 29-item Hamilton depression rating scale (HAM-D-296,7). [123I]Epidepride (185 MBq; MAP Medical Technologies OY, Tikkakoski, Finland) was intravenously injected. The personnel responsible for the SPECT imaging were unaware of the clinical findings. Serial SPECT scans (1 h and 3 h) were performed using a Siemens MultiSPECT 3 gamma camera with
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General population sample (n = 3004) was selected in 1998 and studied in 1999 and 2001
Participants with elevated or low (controls) BDI scores throughout the whole follow-up period were selected for clinical evaluation in 2005
After clinical examination, the SPECT imaging was performed on
Healthy, matched controls (n = 10) with no history of psychiatric illness
First 10 (6 females) with diagnosis of MDD (current: n = 6; partial remission n = 4)
Figure 1. The study setting and selection of participants.
fan-beam collimators (Siemens Medical Systems; Hoffman Estates, IL, USA). Acquisition parameters were 128 ¥ 128 matrix, 40 views/head and each 40 s.4 Region of interest (ROI) placement was based on a Siemens semiautomatic brain quantification program. The lower threshold of 60% of the maximum count was used to reduce the volume averaging and partial volume errors. Our ROI was the temporal cortex, which is large enough for reliable SPECT analysis and also presents the highest extrastriatal epidepride uptake. The cerebellum served as a reference region.8 Specific binding of [123I]epidepride in the ROI was calculated from the average count density from each region as (ROIcerebellum)/cerebellum. The affinity of [123I]epidepride is too high in the basal ganglia, and therefore the equilibrium between striatum and reference region is not obtained within 3.5 h. Magnetic resonance imaging of the brain (1.5 T; Siemens Vision, Erlangen, Germany) was performed to
exclude structural pathology and to provide a three-dimensional neuroanatomic background for the SPECT findings. The Student’s t-test and Mann–Whitney U-test were used to assess differences between the groups. Because of the age-dependant decline in dopamine receptor densities, we used age-adjusted values for our analysis. The correlations between depressive symptoms and D2/3 receptor availability were assessed using Pearson’s correlation coefficient.
RESULTS The MDD group showed a strong correlation between HAM-D-21 scores and D2/3 receptor availability in the temporal cortex bilaterally (Fig. 2; right: r = 0.69, P = 0.03; Fig. 3; left: r = 0.65, P = 0.04). Atypical scores of HAM-D-29 did not correlate with D2/3 receptor availability (right: r = 0.25, P = 0.49; left: r = 0.16, P = 0.66). There were no statistically significant differences between the depressed and controls in D2/3 receptor availability in the temporal cortex (right: t = -1.51, P = 0.15; left: t = -0.73, P = 0.47; Table 1).
DISCUSSION The positive correlation suggests an increase in temporal cortex DA D2/3 binding in the depressed. This
Figure 2. Correlation between right temporal cortex D2/3 receptor binding and HAM-D-21 scores. (•) Partially remitted.
© 2008 The Authors Journal compilation © 2008 Japanese Society of Psychiatry and Neurology
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Table 1. Characteristics of the participants
Age (years) HAM-D-21 scores HAM-D-29 scores Atypical scores of HAM-D-29 D2/3 receptor binding in right temporal cortex D2/3 receptor binding in left temporal cortex † ‡
Depressed participants (n = 10) Mean ⫾ SD
Healthy controls (n = 10) Mean ⫾ SD
P-value
53.10 10.40 12.40 2.00 0.69 0.72
51.60 2.00 2.70 0.70 0.79 0.77
0.63† 0.001‡ 0.001‡ 0.19‡ 0.15† 0.47†
(6.82) (4.86) (6.15) (2.31) (0.12) (0.13)
(6.98) (2.98) (3.56) (1.25) (0.18) (0.17)
Student’s t-test. Mann–Whitney U-test.
may be caused by long-lasting, depression-related decreased postsynaptic dopamine function inducing compensatory up-regulation of D2 receptor density. The finding of no difference between the groups could be explained by the small sample size, possibly leading to a type II statistical error. All MDD participants had a long 7-year history of depressive symptoms, although some were in partial remission at the time of the investigation. Both strengths and weaknesses lay in this study setting. The findings reflect changes induced by a very long-term depressive state. Mild symptoms may have weakened our findings, as the changes in D2/3 receptors would probably be more prominent in more severe depression.
Acute serotonergic blockage as well as drugs affecting cholinergic and GABAergic systems have been reported to increase extrastriatal DA concentrations, possibly leading to up-regulation of DA receptors or increased competition with the tracer.9,10 However, our setting was well controlled for the confounding effect of psychotropic medication. This population-based, exploratory study is the first to demonstrate a correlation between the 21-item Hamilton score and DA D2/3 binding in participants with MDD, suggesting that dopaminergic abnormalities in MDD patients are not limited to striatal areas.
ACKNOWLEDGMENTS SML was supported by the Finnish Graduate School of Psychiatry and an EVO grant from Kuopio University Hospital.
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Figure 3. Correlation between left temporal cortex D2/3 receptor binding and HAM-D-21 scores. (•) Partially remitted.
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