The longitudinal biology of depression : PET studies of the dopamine and serotonin systems

The involvement of monoamine neurotransmission in the pathophysiology of depression was established already in the 1960s. However despite an abundance of research, the exact role of the serotonin (5-HT) and dopamine systems in depression have remained elusive. Positron emission tomography (PET) is a nuclear imaging technique that makes the study of the living human brain possible at a molecular level. In this thesis, PET methods were validated (study I) and applied to study aspects of the serotonin and dopamine systems in depression. This was done through patient and control comparisons (study II and III), through examining correlations between key 5-HT proteins (study IV), and through a longitudinal approach testing patients before and after treatments with known efficacy (study II and III).

In study I, binding characteristics of the D2 dopamine receptor (D2R) radioligand [11C]raclopride was evaluated in brain regions where D2R density is low (i.e., outside striatum). In most extrastriatal brain regions, little or no decrease in binding was observed after administration of a pharmacological competitor, lending no support for valid quantification. Further, extrastriatal test-retest repeatability was poor. The results indicate that [11C]raclopride PET is not suitable for D2R quantification in extrastriatal brain regions.

The aim of study II was to investigate D2R availability in patients with severe depression, compared with healthy controls at baseline and before and after electroconvulsive treatment. Nine patients hospitalized for depression were examined using [11C]raclopride PET before and after a series of electroconvulsive therapy treatments, and nine healthy, matched controls were examined twice. Lower striatal D2R availability was observed in patients compared with controls. No significant change in [11C]raclopride binding was observed in the patient group following treatment. The results suggest that low D2R is associated with severe depression.

In Study III, [11C]MADAM PET was used to quantify the 5-HT transporter (5-HTT) in 17 patients with depression before and after treatment with cognitive behavioral therapy. Matched healthy controls were examined once with [11C]MADAM PET. Depression severity decreased and 5-HTT availability increased significantly in patients following the treatment. No significant difference in [11C]MADAM binding was observed between controls and patients at baseline. The results indicate that previous findings of 5-HT dysregulation in patients with depression reflect a temporary state rather than a permanent trait.

The aim of study IV was to evaluate the correlation between 5-HTT availability and 5-HT 1B receptor (5-HT1B) availability in the human brain. [11C]MADAM and [11C]AZ10419369 PET was used to quantify 5-HTT and 5-HT1B respectively. 17 healthy individuals were examined with both radioligands. Strong correlations were observed in cortical regions while very weak correlations were observed in most subcortical regions. The results could be indicative of a strong transsynaptic regulation of the 5-HT system in cortical regions. However, the analysis was exploratory and [11C]MADAM signal to noise ratio is poor in cortex so the results should be interpreted with caution.

List of scientific papers

I. Svensson JE, Schain M, Plavén-Sigray P, et al. Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain. Neuroimage. 2019; 202: 116143.
https://doi.org/10.1016/j.neuroimage.2019.116143

II. Tiger M, Svensson J, Liberg B, et al. [11C]raclopride positron emission tomography study of dopamine-D2/3 receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects. Psychiatry Clin Neurosci. 2020; 263–269.
https://doi.org/10.1111/pcn.12980

III. Svensson JE, Svanborg C, Plavén-Sigray P, Kaldo V, Halldin C, Schain M, Lundberg J. Serotonin transporter availability increases in patients recovering from a depressive episode. [Submitted]

IV. Svensson JE, Plavén-Sigray P, Halldin C, Schain M, Tiger M, Lundberg J. In vivo correlation of serotonin transporter and 1B receptor availability in the human brain – a PET study. [Manuscript]