Review
Molecular tools for assessing human depression by positron emission tomography

https://doi.org/10.1016/j.euroneuro.2009.04.005Get rights and content

Abstract

We review reports published over the past 5 years on positron emission tomography (PET) of neurotransmission in depressive disorders. The molecular tools of PET neuroimaging are compounds labeled with a positron-emitting nuclide. PET radioligands have been used in recent years to study several aspects of monoaminergic and cholinergic neurotransmission in the brain of depressed subjects and healthy controls. The value of kinetic parameters of certain PET radioligands has often been reported to be lower in depressed subjects than in healthy ones, but there is usually no reliable relationship between the binding potential of the neuroreceptor or transporter and the clinical condition of depressed subject. In addition, many recent PET studies have noted either higher binding potentials in depressed subjects or no difference between binding potentials of depressed and healthy subjects. In our view, recent research has neither proved nor refuted the idea that neuromolecular processes that can be assessed by the radioligands currently available for PET studies of humans are causally related to depressive disorders. The future success of PET research for understanding molecular mechanisms in depressive disorders may therefore require the invention and development of further molecular tools for studying a wider range of neuronal events in the living human brain.

Introduction

Depression causes inner chaos and desperation that requires prompt attention and appropriate care. Success in discovering new, more effective antidepressant therapies may require detailed information on how molecules in the brain can cause and cure depressive disorders in humans. The living brain of humans can now be studied by positron emission tomography PET (Laruelle et al., 2002, Lammertsma, 2002), and that technology has become increasingly popular in psychiatric research. PET makes use of the radioactive decay of positron-emitting nuclides to derive an image of physiological and pharmacological events in a living organ such as the brain. Three types of studies characterize PET research in psychiatry, namely blood flow studies (Ravnkilde et al., 2003, Videbech et al., 2002, Fitzgerald et al., 2006), metabolic studies (Mayberg, 2003, Drevets et al., 2002), and molecular studies. Most molecular PET studies of human depression are based on the monoamine hypothesis (Schildkraut et al., 1968, Schildkraut and Kety, 1967), despite the need for exploring other strategies (Hindmarch, 2002, Berton and Nestler, 2006). The molecular tools for PET studies of human depression are positron-labeled compounds that can identify some aspect of neurotransmission (Fig. 1 and Table 1). This review presents a concise, factual account of PET studies that have used a molecular tool to assess some aspect of neurotransmission in the brain of depressed humans. Only articles published after 2002 are reviewed here (Table 2); excellent reviews of most molecular PET studies published before then are readily available elsewhere (Stockmeier, 2003, Smith et al., 2003, Hesse et al., 2004, Sheline et al., 2004, Meyer, 2007, Dunlop and Nemeroff, 2007, Kasper et al., 2002).

Section snippets

Serotonin synthesis

α-[11C]MTrp

Dopamine synthesis

[18F]Fluoro-L-dopa

Catecholaminergic neurotransmission

[11C]RTI-32

Histamine H1 receptor

[11C]Doxepin

Kano et al. used [11C]doxepin to test the notion that the histaminergic neuron system could be involved in human depression (Kano et al., 2004). They carried out PET scanning with [11C]doxepin in ten male patients with major depressive disorder and 10 healthy, age-matched males. The patients were allowed to take benzodiapines for insomnia and/or fluvoxamine for treatment of depression. PET data analysis used region-of-interest time–activity curves and an average arterial plasma

MAO type A

[11C]Harmine

Muscarinic type 2 receptor

[18F]FP-TZTP

Discussion

The complexity of both depression and PET provide a series of challenges for studying molecular mechanisms of depressive disorders in the living brain. Depression continues to plague populations allover the world, causing major suffering and economic burden. Depression consists of a variety of symptoms including hopelessness, sleep disturbance, altered appetite, lack of energy, concentration difficulties, low self-esteem, self-destructive behavior, painful bodily sensations, and suicidal

Role of the funding source

The authors are employed by the regional government of Middle Jutland that provides the finances required by the hospital-health system. The authors declare that, except for income received from our primary employer, no financial support has been received for preparing this review.

Contributors

Donald F. Smith and Steen Jakobsen

Conflict of interest

The authors declare that, except for income received from our primary employer, no financial support has been received for the writing of this review.

Acknowledgments

We thank everybody at the Center for Psychiatric Research and the PET Center of Aarhus University for providing a positive atmosphere in which to work.

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