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

Molecular imaging of depressive disorders

This chapter summarizes findings of a large number of molecular imaging studies in the field of unipolar and bipolar depression (BD). Brain metabolism in depressed unipolar and bipolar patients is generally hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, the insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Interestingly, after depletion of serotonin or noradrenalin/dopamine in vulnerable (recovered) major depressive disorder (MDD) patients, a similar response pattern in metabolism occurs. Findings on the pre-and postsynaptic dopaminergic system show indications that, at least in subgroups of retarded MDD patients, presynaptic dopaminergic markers may be decreased, while postsynaptic markers may be increased. The findings regarding serotonin synthesis, pre-and postsynaptic imaging can be integrated to a presumable loss of serotonin in MDD, while this remains unclear in BD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. This should be addressed further in future studies. Nevertheless, it should be acknowledged that the serotonergic and dopaminergic systems appear adaptive; therefore, it remains difficult to distinguish state and trait abnormalities. Therefore, future longitudinal molecular imaging studies in the same subjects at different clinical mood states (preferably with different tracers and imaging modalities) are needed to clarify whether the observed changes in transporters and receptors are compensatory reactions or reflect different, potentially causal mechanisms. Several suggestions for future developments are also provided at the end of this chapter.</p

PET-imaging in depression and antidepressant therapies : focus on the serotonin system and the cerebral glucose metabolism

The main scope of the research summarised in this dissertation comprises the use of positron emission tomography to investigate the role of the serotonin transporter in depression and antidepressant therapies. Hereby, several studies were performed using the PET radiotracer [11C]DASB, which specifically targets the serotonin transporter. To allow qualitative and safe research with this radiotracer, the first research topic focussed on the optimization of the radiotracer’s purification procedure and its quality control. Using this radiotracer, a first-in-dog study was carried out to investigate the radiotracer’s distribution and to define the appropriate image quantification methods. Subsequently, this radiotracer was used to perform a dose-occupancy in the dog to estimate the optimal dosing regimen to treat dogs with behavioural disorders with escitalopram. A second part of the dissertation focuses on rats and the current position of repetitive transcranial magnetic stimulation (rTMS) in the rat. Hereby, several additional objectives were put forward. The first objective comprised the evaluation of the accuracy of a for rodents adapted human neuronavigation system to perform rTMS in the rat. A second objective was the investigation of the construct validity of two depression models in terms of altered regional glucose metabolism. This was investigated via a PET study using the radiotracer [18F]FDG. Finally, for the preferred depression model, which was the one based on chronic corticosterone injections, the scope was extended from the serotonin transporter to the serotonin 5-HT1A and 5-HT2A receptors to explore the role of the serotonin system in the pathophysiology of this depression model in the rat. For this purpose, three radiotracers were applied: [11C]DASB, [18F]MPPF, and [18F]altanserin. This allowed to image the serotonin transporters, the 5-HT1A receptors, and the 5-HT2A receptors, respectively

Clinical and PET Imaging Studies in Parkinson’s Disease Motor and Non-Motor Complications: Serotonergic and Dopamimergic Mechanisms and Applications in Treatment

The clinical course of Parkinson’s disease (PD) is complicated by the development of motor and non-motor complications. This thesis, using clinical motor and non-motor assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2 receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor symptoms such as depression and body weight change, (3) striatal serotonergic neurons in levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of treatment with continuous dopaminergic stimulation. The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not in the putamen was evident in PD, possibly accounting for the development of non-motor symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD has been demonstrated in this thesis and showed that serotonergic system is involved early on. (3) Higher serotonin transporter availability has been found in PD patients with elevated depressive symptoms and in PD patients with significant changes in their body weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was found in two PD patients with GIDs who had experienced major recovery after striatal transplantation with fetal cells. GIDs were markedly attenuated by repeated administration of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6) Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical response and stable and prolonged synaptic levels of striatal dopamine release. My observations provide fundamental insight for the role and interaction of serotonergic and dopaminergic systems in the pathophysiology of PD and have key implications for the management of motor and non-motor complications with drugs or cell therapies

Molecular imaging of depressive disorders

This chapter summarizes findings of a large number of molecular imaging studies in the field of unipolar and bipolar depression (BD). Brain metabolism in depressed unipolar and bipolar patients is generally hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Interestingly, after depletion of serotonin or noradrenalin/dopamine in vulnerable (recovered) major depressive disorder (MDD) patients, a similar response pattern in metabolism occurs. Findings on the pre- and postsynaptic dopaminergic system show indications that, at least in subgroups of retarded MDD patients, presynaptic dopaminergic markers may be decreased, while postsynaptic markers may be increased. The findings regarding serotonin synthesis, pre- and postsynaptic imaging can be integrated to a presumable loss of serotonin in MDD, while this remains unclear in BD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. This should be addressed further in future studies. Furthermore, future longitudinal molecular imaging studies in the same subjects at different clinical mood states are needed to clarify whether the observed changes in transporters and receptors are compensatory reactions or reflect different, potentially causal mechanisms. Several suggestions for future developments are also provided.</p

The role of serotonergic and dopaminergic mechanisms and their interaction in Levodopa-induced dyskinesias

Long–term levodopa treatment in Parkinson’s disease (PD) is commonly associated with troublesome levodopa–induced dyskinesias (LIDs). Striatal serotonergic terminals amid the degenerating dopaminergic ones are proposed to play an important role in LIDs by taking up exogenous levodopa and releasing dopamine in an unregulated fashion. However, to date, the underlying mechanisms of LIDs are not fully understood. By using single photon emission computed tomography (SPECT) with 123I–Ioflupane and positron emission tomography (PET) with 11C–DASB and 11C–PE2I, the clinical studies conducted for this thesis aimed (a) to estimate the role of striatal dopamine transporter (DAT) availability in early PD as a prognostic marker for LIDs, (b) to explore whether striatal DAT availability changes over time are related to the appearance of LIDs, (c) to estimate the role of striatal serotonin-to-dopamine transporter (SERT–to–DAT) binding ratios to LIDs, and (d) to look for a relation between the changes in striatal SERT, DAT and SERT–to–DAT binding ratios over time and the appearance of LIDs. The main findings are as follows: (a) in early PD, striatal DAT availability alone does not predict the appearance of future LIDs, (b) at later stages, the occurrence of LIDs may be dependent on the magnitude of DAT decline in the putamen, (c) the SERT–to–DAT binding ratio in the putamen is increased in PD patients as compared to controls, and within PD, it is higher in patients with LIDs as compared to nondyskinetic patients, (d) as PD continues to progress, putaminal serotonergic terminals remain relatively unchanged in comparison to the dopaminergic ones and the aforementioned imbalance (as reflected by the binding ratio) increases over time. These findings provide fundamental insight in the pathophysiology of LIDs and have direct implications for further research towards novel therapeutics in PD dyskinesia.Open Acces

Neurobiological Correlates of Personality Traits: A Study on Harm Avoidance and Neuroticism

Harm Avoidance and Neuroticism are traits that predispose to mental illnesses. Studying them provides a unique way to study predisposition of mental illnesses. Understanding the biological mechanisms that mediate vulnerability could lead to improvement in treatment and ultimately to pre-emptive psychiatry. These personality traits describe a tendency to feel negative emotions such as fear, shyness and worry. Previous studies suggest these traits are regulated by serotonin and opiate pathways. The aim of this thesis was to test the following hypotheses using personality trait measures and positron emission tomography (PET): 1) Brain serotonin transporter density in vivo is associated with Harm Avoidance and Neuroticism traits. 2) μ-opioid receptor binding is associated with Harm Avoidance. In addition, we developed a methodology for studying neurotransmitter interactions in the brain using the opiate and serotonin pathways. 32 healthy subjects who were consistently in either the highest or lowest quartile of the Harm Avoidance trait were recruited from a population-based cohort. Each subject underwent two PET scans, serotonin transporter binding was measured with [11C] MADAM and μ-opioid receptor binding with [11C]carfentanil. We found that the serotonin transporter is not associated with anxious personality traits. However, Harm Avoidance positively correlated with μ-opioid receptor availability. Particularly the tendency to feel shy and the inability to cope with stress were associated μ-opioid receptor availability. We also demonstrated that serotonin transporter binding correlates with μ-opioid receptor binding, suggesting interplay between the two systems. These findings shed light on the neurobiological correlates of personality and have an impact on etiological considerations of affective disorders.Persoonallisuuden neurobiologiset taustatekijät Turvallisuushakuisuus ja neuroottisuus ovat persoonallisuuden piirteitä, joihin liittyy ahdistustaipumus ja joiden on osoitettu altistavan mielenterveyshäiriöille. Tutkimalla näitä persoonallisuuspiirteitä on mahdollisuus saada ainutlaatuista tietoa myös alttiudesta sairastua mielenterveyshäiriöön. Tällaista tietoa voitaisiin käyttää hyväksi psykiatrisen hoidon ja sairauksien ennaltaehkäisyn kehittämiseen. Turvallisuushakuisuus ja neuroottisuus kuvaavat taipumusta kokea negatiivisia tunteita kuten pelkoa, ujoutta ja huolta. Aikaisempien tutkimusten perusteella aivojen serotoniini ja opioidijärjestelmien ajatellaan olevan yhteydessä näihin persoonallisuuden piirteisiin. Tässä väitöskirjatyössä käytettiin positroniemissiotomografia (PET) –tekniikkaa aivojen välittäjäainejärjestelmien toiminnan mittaamiseen ja persoonallisuuskyselyjä (TCI, NEO) persoonallisuuspiirteiden määrittelyyn. Tutkimuksessa testattiin seuraavia hypoteeseja: serotoniinin takaisinottajaproteiini on yhteydessä turvallisuushakuisuuteen, serotoniinin takaisinottajaproteiini on yhteydessä neuroottisuuteen ja μ-opioidireseptori on yhteydessä turvallisuushakuisuuteen. Lisäksi tutkimuksessa kehitettiin menetelmä välittäjäaineverkoston tutkimiseen PET menetelmällä. Tutkimukseen värvättiin laajasta väestöpohjaisesta kohorttitutkimuksesta 32 tervettä koehenkilöä, jotka olivat toistettujen mittausten perusteella turvallisuushakuisuuden suhteen joko ylimmässä tai alimmassa kvartiilissa. Kaikille koehenkilöille tehtiin kaksi PET-kuvausta saman päivän aikana. Ensimmäisessä kuvauksessa käytettiin [11C]MADAM–merkkiainetta mittaamaan serotoniinin takaisinottajaproteiinisitoutumista. Toisessa kuvauksessa käytettiin [11C]karfentaniili–merkkiainetta mittaamaan μ-opioidireseptorisitoutumista. Tämän tutkimuksen perusteella serotoniinin takaisinottajaproteiini ei ollut yhteydessä turvallisuushakuisuuteen eikä neuroottisuuteen. Tutkimuksessa havaittiin kuitenkin positiivinen korrelaatio turvallisuushakuisuuden ja μ-opioidireseptorin välillä. Erityisesti ujous ja taipumus tuntea itsensä turvattomaksi vieraiden ihmisten seurassa sekä kyky selvitä stressistä olivat yhteydessä μ-opioidireseptoriin. Lisäksi serotoniinin takaisinottajaproteiinin havaittiin olevan yhteydessä μ-opioidireseptoriin tietyillä aivoalueilla, jotka liittyvät mieliala- ja ahdistuneisuushäiriöihin. Näitä löydöksiä voidaan tulevaisuudessa hyödyntää mielenterveyshäiriöiden etiologisessa ja mahdollisesti ennaltaehkäisevässä tutkimuksessa.Siirretty Doriast

Innovative Molecular Imaging for Clinical Research, Therapeutic Stratification, and Nosography in Neuroscience.

Over the past few decades, several radiotracers have been developed for neuroimaging applications, especially in PET. Because of their low steric hindrance, PET radionuclides can be used to label molecules that are small enough to cross the blood brain barrier, without modifying their biological properties. As the use of 11C is limited by its short physical half-life (20 min), there has been an increasing focus on developing tracers labeled with 18F for clinical use. The first such tracers allowed cerebral blood flow and glucose metabolism to be measured, and the development of molecular imaging has since enabled to focus more closely on specific targets such as receptors, neurotransmitter transporters, and other proteins. Hence, PET and SPECT biomarkers have become indispensable for innovative clinical research. Currently, the treatment options for a number of pathologies, notably neurodegenerative diseases, remain only supportive and symptomatic. Treatments that slow down or reverse disease progression are therefore the subject of numerous studies, in which molecular imaging is proving to be a powerful tool. PET and SPECT biomarkers already make it possible to diagnose several neurological diseases in vivo and at preclinical stages, yielding topographic, and quantitative data about the target. As a result, they can be used for assessing patients' eligibility for new treatments, or for treatment follow-up. The aim of the present review was to map major innovative radiotracers used in neuroscience, and explain their contribution to clinical research. We categorized them according to their target: dopaminergic, cholinergic or serotoninergic systems, β-amyloid plaques, tau protein, neuroinflammation, glutamate or GABA receptors, or α-synuclein. Most neurological disorders, and indeed mental disorders, involve the dysfunction of one or more of these targets. Combinations of molecular imaging biomarkers can afford us a better understanding of the mechanisms underlying disease development over time, and contribute to early detection/screening, diagnosis, therapy delivery/monitoring, and treatment follow-up in both research and clinical settings