Edited by: Mingzhou Ding, University of Florida, USA
Reviewed by: Xin Di, New Jersey Institute of Technology, USA; Iku Nemoto, Tokyo Denki University, Japan
*Correspondence: Rupert Lanzenberger
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Selective serotonin reuptake inhibitors (SSRIs) modulate serotonergic neurotransmission by blocking reuptake of serotonin from the extracellular space. Up to now, it remains unclear how SSRIs achieve their antidepressant effect. However, task-based and resting state functional magnetic resonance imaging studies, have demonstrated connectivity changes between brain regions. Here, we use positron emission tomography (PET) to quantify SSRI’s main target, the serotonin transporter (SERT), and assess treatment-induced molecular changes in the interregional relation of SERT binding potential (BPND). Nineteen out-patients with major depressive disorder (MDD) and 19 healthy controls (HC) were included in this study. Patients underwent three PET measurements with the radioligand [11C]DASB: (1) at baseline, (2) after a first SSRI dose; and (3) following at least 3 weeks of daily intake. Controls were measured once with PET. Correlation analyses were restricted to brain regions repeatedly implicated in MDD pathophysiology. After 3 weeks of daily SSRI administration a significant increase in SERT BPND correlations of anterior cingulate cortex and insula with the amygdala, midbrain, hippocampus, pallidum and putamen (
The world health organization has estimated some 350 million people of all ages to suffer from major depressive disorder (MDD), which is associated with general disability and increased mortality (World Health Organization,
In recent years, brain network analyses using magnetic resonance imaging (MRI) have evolved as an innovative approach for the characterization of complex structural and functional connections between brain areas (Bassett et al.,
Positron emission tomography (PET) studies commonly directly quantify differences in binding of molecular targets in certain brain regions, e.g., by comparing patients and healthy control subjects. Hence, the
However, even if conditions or groups of subjects may differ in certain characteristics, conducting comparisons of a molecular target solely on a regional level may in some cases not be the appropriate method to capture significant differences (Vanicek et al.,
The mentioned studies focused on specific interactions of the raphe nuclei in the midbrain with serotonergic projection areas. Therefore, we aimed to establish a method for the detection of molecular interregional relationships. These relationships may underline the aforementioned dysregulations proposed in connectivity, reflected by an altered SERT distribution across brain regions in MDD. Thus, unlike the comparison of protein densities in regions of interest (ROIs) and between different conditions or subject groups, we expect general interregional changes that may be associated with the reported alterations in neural circuits in psychiatric disorders, as well as the impact of treatment procedures. Similar approaches analyzing interregional metabolic relations already have been realized previously using PET and [18F]-fluorodeoxyglucose ([18F] FDG; Horwitz et al.,
Previous studies have already reported the considerable reduction of SERT availability during SSRI treatment, expectedly caused by the antidepressant’s occupation of the SERT (Lanzenberger et al.,
Data from 19 subjects (13 female, age range 27–54 years of age, 42.26 ± 7.84) suffering from MDD which has been included in previous publications was analyzed (Lanzenberger et al.,
In this longitudinal study design, patients underwent three PET measurements: first at baseline, second within 6 h after the administration of an oral SSRI dose, and the third measurement after a minimum of 3 weeks (mean time ± SD, 24.73 ± 3.3 days) of daily oral SSRI treatment. The study medication was citalopram (R, S-citalopram, 20 mg/day, nine subjects; Lundbeck A/S, Denmark) or escitalopram (S-citalopram, 10 mg/day, 10 subjects), which constitute frequently prescribed SSRIs that are administered to millions of patients. SERT binding potential (BPND) at baseline, after first and after at least 3 weeks of daily SSRI intake in patients is shown in Figure
PET measurements were performed using a GE Advance full-ring scanner (General Electric Medical Systems, Milwaukee, WI, USA) in 3D mode at the Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine of the Medical University of Vienna. For tissue attenuation correction a transmission scan of 5 min was carried out with 68GE rod sources. PET scans started as [11C]DASB was administered as a bolus injection and total acquisition time was 90 min, split into 15 × 1 min and 15 × 5 min time frames (30 time frames in total). Images were measured in kBq/ccm. Reconstruction occurred in 35 transaxial section volumes (128 × 128) with an iterative filtered backprojection algorithm (FORE-ITER) with a spatial resolution of 4.36 mm full-width at half maximum (FWHM) next to the center of the field of view (Lanzenberger et al.,
PET images were between-frame motion-corrected and summed images were spatially normalized to a [11C]DASB specific template in stereotactic Montreal Institute (MNI) space using SPM8 (Wellcome Trust Centre for Neuroimaging, London, UK
ROIs highly relevant in depression and SSRI treatment were selected based on both, published literature and acceptable signal to noise ratio (SNR) for SERT quantification. These ROIs mainly comprised subcortical regions, i.e., thalamus (Anand et al.,
To test for normality of the BPND values, a Shapiro-Wilk-Test was conducted, which was significant for two variables (data not shown) and due to a sample size of <20, all correlations were calculated using Spearman’s rank correlation.
Molecular relation is here defined as correlation of the SERT density between brain regions, similar to “functional connectivity” in fMRI. However, functional connectivity refers to the temporal coupling of brain regions, whereas for neurotransmitter PET no time sequences are correlated, but molecular density quantities per region pair over the entire group/condition. Correlation matrices were created by calculating Spearman’s rank correlation coefficient (rho;
For the assessment of statistically significant differences in correlations, a 10,000-fold permutation test was performed. For the longitudinal analysis we assured that the measurements from every subject were separated into different conditions (i.e., time points) for each permutation, hence each subject was only assigned once to each condition. For overall comparison the resulting correlation matrices were transformed with Fisher’s r-to-z-transformation. A false discovery rate (FDR) correction with
Interregional SERT correlation matrices for each group and time point can be seen in Figure
Before treatment compared to first treatment (PET 1–PET 2) | |
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ACC | Midbrain (+0.45), pallidum (+0.61), putamen (+0.34) |
Hippocampus | Amygdala (+0.20), insula (+0.37), pallidum (+0.47) |
Insula | Pallidum (+0.56) |
Before treatment compared to ongoing treatment (PET 1–PET 3) | |
---|---|
ACC | Amygdala (+0.49)*, hippocampus (+0.24)*, midbrain (+0.67)*, pallidum (+0.71)*, putamen (+0.49)* |
Insula | Amygdala (+0.47)*, hippocampus (+0.43)*, midbrain (+0.51)*, pallidum (+0.61)*, putamen (+0.36)* |
Hippocampus | Amygdala (+0.24), putamen (+0.23) |
Putamen | Amygdala (+0.36) |
The comparison of MDD at baseline and HC revealed differences in relations only at
Healthy subjects compared to patients with major depressive disorder at baseline (PET 1) | |
---|---|
Hippocampus | Thalamus (−0.23) |
Pallidum | Insula (−0.59), midbrain (0.34) |
In the current study we compared correlations in SERT availability between brain regions relevant in depression. Correlations of the ACC and insula with amygdala, midbrain, hippocampus, pallidum and putamen increased significantly after 3 weeks of SSRI treatment. These results suggest that an interregional rearrangement of SERT availability may contribute to SSRI treatment effects in MDD patients. The fact that a portion of these elevations tend to be present already after 6 h of treatment, may reflect a stabilization of these relations after continuation of SSRI treatment. These results parallel the chronological pattern seen in clinical improvement of MDD symptoms, which often requires several weeks of treatment, whereas only subtle changes can be detected in the initial phase (Taylor et al.,
A number of fMRI studies investigated the influence of SSRIs on activity and functional connectivity. Reduced neural activation in the amygdala was found with fMRI when MDD patients were exposed to emotional, i.e., fearful and sad faces, following 8 weeks of antidepressant treatment (Sheline et al.,
Although the present study could not reveal significant correlations in all of the aforementioned regions, at least a tendency for the most of these was also found in SERT associations. Of those, the ACC and insula were involved in all of the significant correlations. Interestingly, a number of these correlations appear already after 6 h, although not significant at this point. Using rs-fMRI and seed based connectivity analysis, McCabe and Mishor (
Moreover, not only the functional connectivity, but also changes in the regional glucose consumption are of interest. In a PET study assessing the total glucose metabolism with [18F] FDG, a general shift in glucose metabolism was observed with SSRI treatment, namely, an increased glucose metabolism in cortical areas, such as the dorsolateral, ventrolateral, medial prefrontal and parietal cortex, as well as in the dorsal ACC. On the other hand, the left insular cortex, hippocampus and parahippocampal regions showed a decreased consumption after an SSRI treatment period of 6 weeks (Kennedy et al.,
Our current findings suggest that the therapeutic effect of SSRI treatment is mediated by rebalancing SERT in cortical and subcortical areas. In this study interregional changes occurred among the insula and ACC, in association with the midbrain, amygdala, hippocampus, pallidum and putamen. In the light of the present results, we propose that the changes in SERT relations may contribute to a better understanding of the delayed antidepressant effects during SSRI treatment, which may be reflected and influenced by a delayed adjustment of the relationship between interregional SERT densities.
We compared the SERT interregional relations in depressed patients at baseline with those of HC. A recent meta-analysis revealed reduced SERT availability in MDD and highlighted the impact of symptom heterogeneity, which might provide an explanation for contradictory results, when investigating the SERT in MDD patients (Gryglewski et al.,
One limitation of this study is that we did not differentiate between first and recurrent depressive episodes in the MDD patient group. It has been previously proposed that repeated occurrences of episodes may impact on functional connectivity patterns (Veer et al.,
Therefore, a sample size with a minimum of subjects per group is required to maintain statistical power in the application of the permutation test procedure. Thus, the results presented here were not further differentiated by treatment response outcomes, leading to even smaller group sizes. However, a less heterogenic but more extensive patient group could contribute to highlight these differences even more clearly. Further, the consideration of all brain regions, including cortical regions, in this analysis would have allowed to form more global statement in terms of interregional effects on SERT binding. The low SNR due to the sparse SERT density in the most cortical regions although, urge to focus on those regions that show a high binding. However, according to the design of the present study, no evidence can be provided if the elevated correlation of BPND between regions results from an overall decrease of interregional differences due to SERT occupancy. The observation of elevated correlations of BPND between regions may be attributed to this effect, given preserved inter-individual differences in BPND. Finally, the outcomes on interregional relations presented here were determined on group level. Future studies investigating changes in interregional relations based on dynamic PET will enlighten if changes occur also in single subjects.
In the present study we were able to detect changes in interregional correlations of SERT BPND with SSRI treatment in MDD patients, towards a significant increased rearrangement of SERT availability. This finding underlines the concept of interregional changes, rather than mere focal modifications, induced by SSRIs. Our results hereby contribute to a better understanding of SSRI treatment effects.
GMJ designed the methods, analyzed and interpreted the data and wrote main parts of the article. PB-M assisted the measurements and contributed to the study design. CP synthetized the radioligand and edited the manuscript. Support for the statistical implementation was given by GSK. TV assisted the measurements and contributed to the methods of the manuscript. AH gave major technical support, conceptual advice for the methodology and edited the manuscript. GG helped to develop the methodology and edited the manuscript. Advice in all medical concerns and contribution to the discussion and limitations was given by MHi. MS performed the literature search and wrote parts of the discussion. TT-W administered the radioligand and designed the measurements. MM gave technical support and developed the radioligand together with WW, which also planned the production. MHa provided the facilities for the radioligand synthesis and gave conceptual advice. SK supervised the entire experiment and patient care. RL developed the concept of the research question, provided funding and revised the manuscript. All authors discussed the results and implications and commented on the manuscript at all stages.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This scientific project and reevaluation of data were performed with the support of the Medical Imaging Cluster of the Medical University of Vienna. Personal costs were partly funded by the Austrian Science Fund (FWF) Grant 27141, the Austrian National Bank (OeNB Anniversary Fund No. 11468) to RL, PET measurements and treatment were supported by an investigator-initiated and unrestricted research grant (11821) from H. Lundbeck A/S, Denmark to SK. H. Lundbeck A/S, FWF and OeNB had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report and in the decision to submit the article for publication. GG is recipient of a DOC Fellowship of the Austrian Academy of Sciences at the Institute of Psychiatry and Psychotherapy, Medical University of Vienna. The authors thank the medical and technical teams of the PET Center at the Medical University of the Vienna (D. Haeusler, G. Karanikas, K. Kletter, G. Wagner, B. Reiterits, I. Leitinger, R. Bartosch), the psychiatrists of the Department of Psychiatry and Psychotherapy of the Medical University of Vienna (A.S. Höflich, C. Kraus, D. Winkler, E. Akimova, C. Spindelegger, M. Fink, U. Moser, M. Willert) and H. Sitte from the center for physiology and pharmacology of the Medical University of Vienna. Parts of this study have been presented by G.M. James at the 28th European College of Neuropsychopharmacology (ECNP), August 29–September 1, 2015, Amsterdam, Netherlands.
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