From THE DEPARTMENT OF CLINICAL NEUROSCIENCE Karolinska Institutet, Stockholm, Sweden PET STUDIES OF THE SEROTONIN SYSTEM IN MAJOR DEPRESSION AND ITS TREATMENT

Cover picture: Summation PET images of an untreated reference subject (left) and of a patient treated with an SSRI (citalopram, right), after intravenous injection of [ 11 C]MADAM. All previously published papers were reproduced with permission from the publisher. ABSTRACT 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. [ 11 C]MADAM is an established radioligand selective for the serotonin transporter, and [ 11 C]AZ10419369 is selective for the 5-HT 1B 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 [ 11 C]AZ10419369 better we examined the sensitivity of this radioligand to baseline serotonin levels. In study I we examined serotonin transporter occupancy with PET and [ 11 C]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 of internet-delivered cognitive behavioural therapy (CBT) for recurrent major depressive disorder on [ 11 C]AZ10419369 binding. Ten patients with an ongoing and untreated major depressive episode finished the study according to protocol and were examined with PET and [ 11 C]AZ10419369 before and after CBT. All patients responded to treatment. The binding potential, BP ND , was reduced by 33 % in the dorsal brain stem, which included the raphe nuclei, from which the serotonergic neurons project. Since the 5-HT 1B receptor acts inhibitory, a reduction of 5-HT 1B receptor density in the raphe nuclei would in theory result in a general stimulation of …