PET studies of the serotonin system in major depression and its treatment
Year: 2014
Type: dissertation
Abstract: The serotonin system has been implicated in major depression since the \n1960s, mainly based on the serotonin enhancing properties of \nantidepressants. Positron emission tomography, PET, is the in vivo \nmolecular imaging method with the best spatial resolution. There has \nbeen a gradual development of suitable radioligands for serotonergic \ntargets since the mid-1990s, widening the scope of PET studies of the \nserotonin system. MADAM is an established radioligand selective for \nthe serotonin transporter, and AZ10419369 is selective for the \n5-HT1B receptor. \n \n \n \nThe aim of this thesis was to study the serotonin \nsystem in major depressive disorder and the serotonergic effects of \ntreatment with antidepressive medication or with psychotherapy. In order \nto understand the results with AZ10419369 better we examined the \nsensitivity of this radioligand to baseline serotonin levels. \n \n \n \nIn study I we examined serotonin transporter occupancy with PET and MADAM \nin responders to treatment with seven different antidepressants in \ndifferent doses. Two tricyclic antidepressants (TCAs) and four selective \nserotonin reuptake inhibitors (SSRIs) were examined. Mirtazapine was \nincluded as a serotonin transporter “dummy”. Serotonin transporter \noccupancy could be confirmed in vivo for all TCAs and SSRIs. There was \nno significant difference in serotonin transporter occupancy between the \nold antidepressants, TCAs, and the new, SSRIs. Mirtazapine did not \noccupy the serotonin transporter. The average serotonin transporter \noccupancy in SSRIs and TCAs was 67 %, which was significantly lower \nthan the 80 % serotonin transporter occupancy previously postulated \nimportant for SSRI effect. \n \n \n \nIn study II we investigated the effect ofinternet-delivered cognitive \nbehavioural therapy (CBT) for recurrent \nmajor depressive disorder on AZ10419369 binding. Ten patients with \nan ongoing and untreated major depressive episode finished the study \naccording to protocol and were examined with PET and AZ10419369 \nbefore and after CBT. All patients responded to treatment. The binding \npotential, BPND, was reduced by 33 % in the dorsal brain stem, which \nincluded the raphe nuclei, from which the serotonergic neurons project. \nSince the 5-HT1B receptor acts inhibitory, a reduction of 5-HT1B \nreceptor density in the raphe nuclei would in theory result in a general \nstimulation of the serotonin system. There were no other significant \nchanges in radioligand binding in the brain with CBT. \n \n \n \nIn study III we \nwanted to compare AZ10419369 binding in patients with an ongoing \nand untreated major depressive episode within recurrent major depressive \ndisorder with age- and sex matched controls. Ten patients and ten \ncontrols were examined with PET and AZ10419369. AZ10419369 \nbinding was lower in the anterior cingulate cortex (25 % lower) and \nassociated regions (20 % lower in the subgenual prefrontal cortex and \n45 % lower in the hippocampus). The difference in the anterior cingulate \ncortex survived Bonferroni correction for multiple comparisons. The \nanterior cingulate cortex is an established part of the neurocircuitry \nof depression. There were no significant differences in the other \nexamined brain regions. 3 \n \n \n \nIn study IV we correlated AZ10419369 \nbinding with concentrations of serotonin and its metabolite \n5-Hydroxyindoleacetic Acid (5-HIAA) in the cerebrospinal fluid (CSF) at \nbaseline in healthy subjects. Twelve healthy subjects without \npsychiatric history were first examined with PET and AZ10419369 and \nthen with lumbar puncture for CSF analysis. The CSF concentrations of \nserotonin and 5-HIAA were determined with high performance liquid \nchromatography. There were no significant correlations between levels of \nserotonin and 5-HIAA in the CSF and AZ10419369 binding in the whole \nbrain, in the caudate nucleus or in the occipital cortex. Since \ncorrelations between CSF and brain concentrations of serotonin and \n5-HIAA have been demonstrated, AZ10419369 binding at baseline \nlikely reflects 5-HT1B receptor density. This has bearing for the \ninterpretation of study II and III.
Source: Figshare
Author: Mikael Tiger
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1505675379