Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: Reduction by a selective serotonin reuptake inhibitor
Esler M, Lambert E, Alvarenga M,Socratous F, Richards J, Barton D, el al.;
Commented by , 28 Sep 2007
Aim of the study
Do people with panic disorder have disrupted central serotonin and/or noradrenaline turnover compared to healthy controls?
Method
Participants were 34 people who met the DSM-IV criteria for panic disorder and 24 controls matched for age and body mass index. Panic disorder participants were medication naive or had not used medication for 3 months prior to testing. Any co-morbid psychiatric diagnosis was secondary and considered mild. Severity of panic disorder was assessed using the patient self rating Panic Disorder Severity Scale (PDSS) and the Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV) administered by the clinician.
An additional 10 patients with panic disorder were tested prior to citalopram (20 – 60 mg) treatment, and again after a minimum of three months remission or partial remission. Six of these participants received cognitive behavioural therapy in addition to citalopram.
Central venous and arterial blood was sampled simultaneously via a catheter inserted high in the internal jugular vein and cannula in the radial or brachial artery, respectively. These samples were assayed for noradrenaline, DHPG, MHPG (noradrenaline metabolites), and 5-HIAA (5-HT metabolite). Serotonin transporter genotyping was also conducted.
Results
5-HIAA jugular venous overflow in panic patients was 4 times greater than in controls (p < 0.01). PDSS scores showed a strong, positive association with serotonin turnover (r= 0.86, p<0.001). Patients successfully treated with citalopram demonstrated a reduced turnover rate compared with levels prior to treatment (p<0.01). There was no difference in brain serotonin turnover between ss, sl or ll genotypes (see 1 for information on serotonin transporter genotypes in anxiety) in people with panic disorder.
No differences between panic disorder patients and controls in brain noradrenaline turnover indices were observed.
Dr Hood's and Prof Nutt's comments
The results presented here demonstrate (ref. 1) a marked increase in central serotonin turnover in people with panic disorder that (ref. 2) does not appear to be related to differences in re-uptake transporter function and (ref. 3) a normalisation of 5-HT turnover by successful treatment with the SSRI citalopram.
As the authors 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 this way was made, quite rightly, on ethical grounds. Nonetheless, these observations provide an important piece of the serotonin hypothesis of panic puzzle.
Two competing theories for the role of serotonin in panic exist (ref. 2). The first, the serotonin deficit theory, proposes that too little serotonin has an etiological role in panic disorder, and that SSRIs are effective as they increase synaptic serotonin. A process known as Tryptophan Depletion (TD) can be used to decrease 5-HT transiently by dietary restriction of the serotonin precursor tryptophan (ref. 3).
TD increases the likelihood of panic following challenge in untreated and SSRI treated panic disorder, which is consistent with low synaptic 5-HT being associated with panic disorder. 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. have speculated that higher 5-HT turnover is a consequence of increased raphe cell firing and equates to increased postsynaptic receptor occupancy by 5HT. This interpretation of these results lends itself nicely to the serotonin excess theory. It is difficult, however to reconcile the tryptophan depletion studies under these assumptions.
The theory does however fit with data that there is a reduction in PET binding of the 5HT 1A receptor tracer [11C]-WAY 100635 in the raphe in patients with panic disorder; less receptors would mean less inhibitory control of the raphe (ref. 4).
A possibility is that that the higher 5-HT turnover demonstrated in this study does not necessarily equate to increased receptor occupancy. If, however, patients with panic disorder are metabolising 5-HT at 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.
In this model the SSRIs work to increase synaptic 5HT and the reduction in turnover is due to a reduction in firing secondary to increased 5HT in the synapse increasing inhibition through the 5HT auto receptors. Previous work using peripheral markers has suggested that noradrenaline uptake blocking antidepressants increase noradrenaline synaptic efficiency in depression in this way (ref. 5).
Despite substantial advances in our understanding of 5-HT in panic, we still do not know whether increased or decreased serotonergic throughput is associated with this illness. In a previous commentary (ref. 6) we discussed the reticence of psychiatric researchers to use invasive experimental methodology.
It is likely that further advances into this area will require similar methodologies to get closer to the aspect we are trying to measure. Assessing the specificity of high 5-HT turnover for panic disorder by measuring central 5-HT turnover in patients with anxiety disorders and depression may help us clarify the role of 5-HT in these prevalent and impairing conditions.
References
1. Hood S, Nutt DJ. Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders. May 2007
2. Hood SD, Argyropoulos SV, Nutt DJ. New directions in the treatment of anxiety disorders. Expert Opinion on Therapeutic Patents 2003; 13 (4); 401-424
3. Hood SD, Bell CJ, Nutt DJ. Acute tryptophan depletion. Part I: rationale and methodology. Australian and New Zealand Journal of Psychiatry 2005; 39 (7); 558-564
4. Nash J, Sargent P, Rabiner E, Hood SD, Argyropoulos SV, Grasby P et al. Altered 5HT1A binding in panic disorder demonstrated by PET scanning. Journal of Psychopharmacoly 2003; 17 (3); A30
5. Hauger RL, Scheinin M, Siever LJ, Linnoila M, Potter WZ. Dissociation of norepinephrine turnover from alpha-2 responses after clorgiline. Clinical Pharmacology & Therapeutics 1988; 43 (1); 32-38
6. Hood S, Nutt DJ. Basilar artery blood flow velocity changes in patients with panic disorder following 35% carbon dioxide challenge. March 2007