Smith, 2007 Receptor occupancy of mirtazapine determined by PET in healthy volunteers.

[Altostrata]

Psychopharmacology (Berl). 2007 Nov;195(1):131-8. Epub 2007 Jul 25.

Receptor occupancy of mirtazapine determined by PET in healthy volunteers.
Smith DF¹, Stork BS, Wegener G, Jakobsen S, Bender D, Audrain H, Jensen SB, Hansen SB, Rodell A, Rosenberg R.

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/17653532


RATIONALE:
Molecular tools are needed for assessing anti-depressant actions by positron emission tomography (PET) in the living human brain.

OBJECTIVES:
This study determined whether [(11)C]mirtazapine is an appropriate molecular tool for use with PET to estimate the magnitude of neuroreceptor occupancy produced by daily intake of mirtazapine.

METHODS:
This study used a randomised, double-blind, placebo-controlled, parallel-group, within-subject design. Eighteen healthy volunteers were PET-scanned twice with [(11)C]mirtazapine; once under baseline condition and again after receiving either placebo or mirtazapine (7.5 or 15 mg) for 5 days. We determined kinetic parameters of [(11)C]mirtazapine in brain regions by the simplified reference region method and used binding potential values to calculate receptor occupancy produced by mirtazapine.

RESULTS:
Serum concentrations of mirtazapine ranged from 33 to 56 nmol/l after five daily doses of 7.5 mg mirtazapine and were between 41 and 74 nmol/l after 15 mg mirtazapine. Placebo treatment failed to alter the binding potential of [(11)C]mirtazapine from baseline values, whereas daily intake of mirtazapine markedly decreased the binding potential in cortex, amygdala and hippocampus. Receptor occupancy ranged from 74 to 96% in high-binding regions of the brain after five daily doses of 7.5 mg or 15 mg mirtazapine, whereas 17-48% occupancy occurred in low-binding regions.

CONCLUSIONS:
[(11)C]Mirtazapine together with PET can determine the degree of receptor occupancy produced by daily doses of mirtazapine in regions of the living human brain.

 

 

From the paper:

....

The main finding of the present study is that PET scanning with [11C]mirtazapine provides a reliable, non- invasive procedure for determining the magnitude of receptor occupancy in selected regions of the human brain during mirtazapine therapy. The relatively short-term treatment used in the present study was selected for practical reasons, in that 4–6 days of mirtazapine therapy usually leads to steady state levels of the drug in the bloodstream (Timmer et al. 2000; Timmer et al. 1996). It is important to note that the present results were obtained in healthy subjects with no history of disease whatsoever, and that the degree of receptor occupancy cause by mirtazapine in depressed patients is currently unknown. In the clinic, mirtazapine is typically given at a starting dose of 15 mg in the evening for 1–2 weeks, followed by a gradual increase over 2–4 weeks to a daily dose of 45 mg (Stahl 2006; Stimmel et al. 1997). Serum concentrations of mirtazapine typically range between 40 and 60 nmol/l at steady state with daily dose of 15 mg, as in the present study, whereas they rise to between 100 and 200 nmol/l after daily mirtazapine doses of 30–45 mg (Reis et al. 2005).

....

Sedation is often reported by patients given 15 mg of mirtazapine, and it may appear at even lower doses (Stahl 2006). We noted that four of the six healthy subjects given 7.5 mg mirtazapine in the present double-blind study reported being more tired than normal during the treatment. However, three of the six healthy subjects given placebo also reported being more tired than usual during treatment, so we cannot attribute tiredness only to effects of mirtazapine in the present study. On the other hand, an unexpected side effect, namely increased irritability, was reported only by subjects given mirtazapine. As an example, one such subject described feeling unusually upset when her boyfriend left his coffee cup on that kitchen table rather than putting it over by the sink to be washed. We cannot account for this effect of mirtazapine in our healthy subjects, although it may be related to activating actions of the drug via accelerated release of noradrenaline and dopamine in corticolimbic structures (Millan 2006).....