Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: Reduction by a selective serotonin reuptake inhibitor

Abstract

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

Evaluation of the Brain 5-HT2A Receptor Binding Index in Dogs with Anxiety Disorders, Measured with 123I-5I-R91150 and SPECT

“…Evidence of an increased serotonin turnover in patients with depression and panic disorders was provided in a study that reported an increased 5-hydroxyindoleacetic acid level in the internal jugular venous plasma (30). Using in vivo microdialysis, we demonstrated in rats that conditioned fear stress resulted in increased extracellular serotonin in the medial frontal cortex.…”

Pharmacological modulation of anxiety-like phenotypes in adult zebrafish behavioral models

“…Since selective serotonin reuptake inhibitors (SSRIs) are potent modulators of brain serotonin (Esler et al, 2007;Goldstein and Goodnick, 1998), behavioral effects of fluoxetine on zebrafish merit further scrutiny. Zebrafish possess a well-developed serotonergic system which makes them an ideal model for such analyses.…”

Comment on Esler et al. () “Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: Reduction by a selective serotonin reuptake inhibitor”

“…The results presented in the study by Esler et al (2007) demonstrate a marked increase in central serotonin turnover in people with panic disorder that does not appear to be related to differences in reuptake transporter function (Hood et al , 2005, and a normalisation of 5-HT turnover by successful treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. As Esler et al suggest, it is not possible to rule out the alternative explanation that the SSRI treatment effects are a consequence of repeated testing, but the decision to design the study in the way that they used was made, quite rightly, on ethical grounds.…”

“…A possibility is that the higher 5-HT turnover demonstrated in the Esler et al (2007) study does not necessarily equate to increased receptor occupancy. If, however, patients with panic disorder are metabolising 5-HTat a greater rate than controls, then one might see high turnover but low effective occupancy; in keeping with the TD-supported hypothesis that a relative underfunctioning through low levels of synaptic 5-HT are associated with panic.…”

“…The competing theory, that there is too much 5-HT, suggests that SSRIs work by reducing 5-HT turnover via increasing inhibitory action at autoreceptors, thereby decreasing 5-HT and producing the therapeutic effect. Esler et al (2007) have speculated that higher 5-HT turnover is a consequence of increased raphe nucleus cell firing and equates to increased postsynaptic receptor occupancy by 5-HT. This interpretation of their results lends itself nicely to the serotonin excess theory.…”