Links between sleep and depression are strong. About three quarters of depressed patients have insomnia symptoms, and hypersomnia is present in about 40% of young depressed adults and 10% of older patients, with a preponderance in females. The symptoms cause huge distress, have a major impact on quality of life, and are a strong risk factor for suicide. As well as the subjective experience of sleep symptoms, there are well-documented changes in objective sleep architecture in depression. Mechanisms of sleep regulation and how they might be disturbed in depression are discussed. The sleep symptoms are often unresolved by treatment, and confer a greater risk of relapse and recurrence. Epidemiological studies have pointed out that insomnia in nondepressed subjects is a risk factor for later development of depression. There is therefore a need for more successful management of sleep disturbance in depression, in order to improve quality of life in these patients and reduce an important factor in depressive relapse and recurrence.

Molecular in vivo neuroimaging techniques can be used to measure regional changes in endogenous neurotransmitters, evoked by challenges that alter synaptic neurotransmitter concentration. This technique has most successfully been applied to the study of endogenous dopamine release using positron emission tomography, but has not yet been adequately extended to other neurotransmitter systems. This review focuses on how the technique has been applied to the study of the 5-hydroxytryptamine (5-HT) system. The principles behind visualising fluctuations in neurotransmitters are introduced, with reference to the dopaminergic system. Studies that aim to image acute, endogenous 5-HT release or depletion at 5-HT receptor targets are summarised, with particular attention to studies in humans. Radiotracers targeting the 5-HT 1A , 5-HT 2A , and 5-HT 4 receptors and the serotonin reuptake transporter have been explored for their sensitivity to 5-HT fluctuations, but with mixed outcomes; tracers for these targets cannot reliably image endogenous 5-HT in humans. Shortcomings in our basic knowledge of the mechanisms underlying changes in binding potential are addressed, and suggestions are made as to how the selection of targets, radiotracers, challenge paradigms, and experimental design might be optimised to improve our chances of successfully imaging endogenous neurotransmitters in the future.

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging.

Alcohol use disorder (AUD) is a leading cause of morbidity and mortality. 1-2 Alcohol consumption is related to approximately 4% of the global burden of disease. 1 It has been estimated that, in clinical settings and compared to the general population, the relative risk of mortality is 3.38 for male patients and 4.57 for female patients with AUD. 2 Patients who reduce their alcohol consumption may halve this increased risk of mortality compared to patients with AUD who do not. 3 However, currently the approved pharmacotherapies that may help patients with AUD to achieve abstinence and/or reduce alcohol consumption to lower drinking levels are limited in number and efficacy. 4-5 Therefore, there is an urgent need to develop more effective treatments in this area. Preclinical and human studies suggest that baclofen, a GABA B receptor agonist, might be a novel treatment for patients with moderate to severe AUD. 6 Notably, a few years after initial randomized clinical trials (RCTs) were conducted, the potential use of this medication for AUD dramatically increased in its popularity due to a French case report describing the use of very high doses of baclofen to treat alcohol craving and drinking. 7 This intriguing yet purely anecdotical case report led to significant scientific and mass media attention and to the use of baclofen (off-label) in the treatment of AUD, such that the French drugs regulatory agency became involved in evaluating the use of baclofen in AUD. However, clinical studies conducted in Europe, USA, Australia, Israel and that evaluated baclofen efficacy in AUD have yielded conflicting results with some but not all RCTs showing an effect of baclofen. 6 The three recent meta-analyses do not draw definitive conclusions on the efficacy of baclofen in the treatment of AUD. 8-10 In fact, one meta-analysis 8 found no significant superiority of baclofen over placebo on the outcomes of each study whereas the other two found that baclofen treatment significantly increased the rate of abstinent patients 9-10 and time to first lapse 9 compared to placebo. Furthermore, one meta-analysis found larger effect sizes of baclofen among heavy drinkers and studies using lower doses. 9 The other study found no significant efficacy of baclofen in reducing the severity of craving for alcohol, anxiety, and depression. 10 In addition, these two meta-analyses reported no significant efficacy of baclofen on other important outcomes such as rate of abstinence days 9-10 or rate of heavy drinking days. 10 Chiefly, all three meta-analyses found overall a small effect size and substantial heterogeneity among studies. 8-10 Following the publication of these metaanalyses, 8-10 a further RCT has been completed and data analysis is currently under way (JC Garbutt, unpublished; ClinicalTrials.gov: NCT01980706). Despite the lack of consistent evidence of efficacy, baclofen is frequently used off-label to treat AUD, especially in some European countries and Australia. However, there is significant variability in the use of baclofen for cl...

This model therefore provides a promising paradigm in which we can study novel treatments for sleep disorders and an opportunity for direct comparison of results between rodents and humans.