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 studyI 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