PET studies of the serotonin system in major depression and its treatment

The serotonin system has been implicated in major depression since the 1960s, mainly based on the serotonin enhancing properties of antidepressants. Positron emission tomography, PET, is the in vivo molecular imaging method with the best spatial resolution. There has been a gradual development of suitable radioligands for serotonergic targets since the mid-1990s, widening the scope of PET studies of the serotonin system. MADAM is an established radioligand selective for the serotonin transporter, and AZ10419369 is selective for the 5-HT1B receptor.

The aim of this thesis was to study the serotonin system in major depressive disorder and the serotonergic effects of treatment with antidepressive medication or with psychotherapy. In order to understand the results with AZ10419369 better we examined the sensitivity of this radioligand to baseline serotonin levels.

In study I we examined serotonin transporter occupancy with PET and MADAM in responders to treatment with seven different antidepressants in different doses. Two tricyclic antidepressants (TCAs) and four selective serotonin reuptake inhibitors (SSRIs) were examined. Mirtazapine was included as a serotonin transporter “dummy”. Serotonin transporter occupancy could be confirmed in vivo for all TCAs and SSRIs. There was no significant difference in serotonin transporter occupancy between the old antidepressants, TCAs, and the new, SSRIs. Mirtazapine did not occupy the serotonin transporter. The average serotonin transporter occupancy in SSRIs and TCAs was 67 %, which was significantly lower than the 80 % serotonin transporter occupancy previously postulated important for SSRI effect.

In study II we investigated the effect ofinternet-delivered cognitive behavioural therapy (CBT) for recurrent major depressive disorder on AZ10419369 binding. Ten patients with an ongoing and untreated major depressive episode finished the study according to protocol and were examined with PET and AZ10419369 before and after CBT. All patients responded to treatment. The binding potential, BPND, was reduced by 33 % in the dorsal brain stem, which included the raphe nuclei, from which the serotonergic neurons project. Since the 5-HT1B receptor acts inhibitory, a reduction of 5-HT1B receptor density in the raphe nuclei would in theory result in a general stimulation of the serotonin system. There were no other significant changes in radioligand binding in the brain with CBT.

In study III we wanted to compare AZ10419369 binding in patients with an ongoing and untreated major depressive episode within recurrent major depressive disorder with age- and sex matched controls. Ten patients and ten controls were examined with PET and AZ10419369. AZ10419369 binding was lower in the anterior cingulate cortex (25 % lower) and associated regions (20 % lower in the subgenual prefrontal cortex and 45 % lower in the hippocampus). The difference in the anterior cingulate cortex survived Bonferroni correction for multiple comparisons. The anterior cingulate cortex is an established part of the neurocircuitry of depression. There were no significant differences in the other examined brain regions. 3

In study IV we correlated AZ10419369 binding with concentrations of serotonin and its metabolite 5-Hydroxyindoleacetic Acid (5-HIAA) in the cerebrospinal fluid (CSF) at baseline in healthy subjects. Twelve healthy subjects without psychiatric history were first examined with PET and AZ10419369 and then with lumbar puncture for CSF analysis. The CSF concentrations of serotonin and 5-HIAA were determined with high performance liquid chromatography. There were no significant correlations between levels of serotonin and 5-HIAA in the CSF and AZ10419369 binding in the whole brain, in the caudate nucleus or in the occipital cortex. Since correlations between CSF and brain concentrations of serotonin and 5-HIAA have been demonstrated, AZ10419369 binding at baseline likely reflects 5-HT1B receptor density. This has bearing for the interpretation of study II and III.

List of scientific papers

I. Johan Lundberg, Mikael Tiger, Mikael Landén, Christer Halldin, and Lars Farde. Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder. The International Journal of Neuropsychopharmacology. 2012 Sep;15(8):1167-72.
https://doi.org/10.1017/S1461145711001945.

II. Mikael Tiger, Christian Rück, Anton Forsberg, Andrea Varrone, Nils Lindefors, Christer Halldin, Lars Farde, and Johan Lundberg. Reduced 5-HT1B receptor binding in the dorsal brain stem after cognitive behavioural therapy of major depressive disorder. Psychiatry Research: Neuroimaging. 2014 Aug 30, 223(2):164-70.
https://doi.org/10.1016/j.pscychresns.2014.05.011.

III. Mikael Tiger, Christian Rück, Andrea Varrone, Nils Lindefors, Christer Halldin, Lars Farde, and Johan Lundberg. Lower serotonin1B receptor binding potential in the anterior cingulate cortex in major depressive disorder. [Manuscript]

IV. Mikael Tiger, Per Svenningsson, Magdalena Nord, Sandra Jabre, Christer Halldin, and Johan Lundberg. No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [11C]AZ10419369 binding measured with PET in healthy volunteers. Synapse. 2014, Oct;68(10):480-3.
https://doi.org/10.1002/syn.21761.