Brief report

Brain fluoxetine measurements using fluorine magnetic resonance spectroscopy in patients with social phobia

Social anxiety disorder is characterized by aberrant socio-emotional information-processing and affect regulation in the context of social evaluative threat and self-referential processing. Several neurobiological systems are likely to be implicated in the pathophysiology of the disorder, including the stress response system as shown by studies of psychoneuroendocrinology and cognitive-affective systems elucidated by studies of brain function. In this chapter, we provide a qualitative review and synthesis of the extant literature on the neuroendocrinology and neuroanatomy of social anxiety disorder that spans the past two decades.

Brain imaging techniques allow the in vivo evaluation of the human brain, leading to a better understanding of its anatomical, functional and metabolic substrate. The aim of this current report is to present a systematic and critical review of neuroimaging findings in Social Anxiety Disorder (SAD). A literature review was performed in the PubMed Medline, Scielo and Web of Science databases using the following keywords: ‘MRI’, ‘functional’, ‘tomography’, ‘PET’, ‘SPECT’, ‘spectroscopy’, ‘relaxometry’, ‘tractography’ and ‘voxel’ crossed one by one with the terms ‘social anxiety’ and ‘social phobic’, with no limit of time. We selected 196 articles and 48 of them were included in our review. Most of the included studies have explored the neural response to facial expressions of emotion, symptoms provocation paradigms, and disorder-related abnormalities in dopamine or serotonin neurotransmission. The most coherent finding among the brain imaging techniques reflects increased activity in limbic and paralimbic regions in SAD. The predominance of evidence implicating the amygdala strengthens the notion that it plays a crucial role in the pathophysiology of SAD. The observation of alterations in pre-frontal regions and the reduced activity observed in striatal and parietal areas show that much remains to be investigated within the complexity of SAD. Interesting, follow-up designed studies observed a decrease in perfusion in these same areas after either by pharmacological or psychological treatment. The medial prefrontal cortex provided additional support for a corticolimbic model of SAD pathophysiology, being a promising area to investigation. Furthermore, the dopaminergic and GABAergic hypotheses seem directed related to its physiopathology. The present review indicates that neuroimaging has contributed to a better understanding of the neurobiology of SAD. Although there were several methodological differences among the studies, the global results have often been consistent, reinforcing the evidence of a specific cerebral circuit involved in SAD, formed by limbic and cortical areas.

Substantial advances have been made in the neurobiology of stress and of fear from animal, lesion, and human studies. By extension, these advances have been translated into clinical investigations of patients with social anxiety disorder (SAD). This chapter provides a qualitative review and synthesis of the extant literature on the neuroendocrinology and neuroanatomy of SAD. Neurobiological investigations of SAD, a disorder of abnormal fear of social and performance situations, show that evidence of neuroendocrine dysregulation in response to stress though the pattern of cortisol reactivity has been inconsistent. Moreover, anomalous reactivity may be limited to a subset of individuals with SAD and may reflect individual variability in the stress response. The finding that early aversive experiences contribute to cortisol reactivity in SAD and the possibility that individual differences in coping style may affect cortisol levels suggest that more study in the area of individual differences in HPA axis reactivity and their relation to social anxiety is warranted.

Magnetic resonance (MR) provides an attractive non-invasive way of studying drug distribution in vivo. Widespread occurrence of fluorine in medicinal compounds, and its favourable MR properties, make it an effective probe for drug absorption, distribution, metabolism and excretion (ADME) studies. We discuss practicalities of detection and localization, and when ¹⁹F MR would add value in a clinical trial, exemplified by deployments in oncology and psychiatry, where it is a practical way of demonstrating chronic brain accumulation directly. Limitations are emphasized to minimize failure risk, for example, inadequate sensitivity relative to tissue drug concentrations. The review anticipates increasing clinical ¹⁹F MR as high field human scanners become widespread, and requirements to demonstrate mechanisms underlying clinical effects become more pressing.

Chronic mild stress (CMS) procedure was used to study an antidepressant-like activity of AGN 2979, a selective inhibitor of tryptophan hydroxylase (TH) activation. At the dose of 4 mg/kg, AGN 2979 fully reversed the CMS-induced reduction in the consumption of 1% sucrose solution. This effect was maintained for at least 1 week after cessation of treatment and no signs of withdrawal were observed in either stressed or control animals receiving AGN 2979. The lower (1 mg/kg) and higher (16 mg/kg) doses were ineffective. The magnitude of action of AGN 2979 in the CMS model was comparable to that of imipramine (10 mg/kg) but its onset of action appears to be faster since the inhibition of sucrose intake in stressed animals was already reversed after the 1st week of AGN 2979 administration while imipramine required 3 weeks of treatment to cause similar effect. These results provide support for the hypothesis that inhibition of TH activation may result in a potent antidepressant activity.

This investigation of fluvoxamine and fluoxetine-norfluoxetine distributions in vivo at steady-state and of quantitative kinetics in brain and plasma after drug therapy interruption was performed by fluorine nuclear magnetic resonance spectroscopy (¹⁹F MRS), spectroscopic imaging (MRSI), and plasma HPLC on 12 subjects treated for depression. MRSI suggests a homogeneous distribution of ¹⁹F MRS visible fluvoxamine mainly in brain. Fluvoxamine steady-state brain concentrations (12 ± 5 μM; n = 13) and brain-to-plasma concentration ratios (10 ± 2; n = 12) were similar to those of combined fluoxetine-norfluoxetine (CF-norfluoxetine) (13 ± 6 μM; n = 4 and 10 ± 6; n = 4). Fluvoxamine brain elimination half-life (79 ± 24 hours; n = 4) was significantly shorter than that of CF-norfluoxetine (382 ± 48 hours; n = 2). Fluvoxamine brain-to-plasma-half-life-ratio was 2.2 ± 0.3 (n = 4), contrarily to CF-norfluoxetine (1.0 ± 0.3; n = 2). This study shows that quantitative pharmacokinetics in target organs by ¹⁹F MRS in vivo should prove useful for understanding and investigating outcome of treatment modifications and side effects.