Elsevier

Biological Psychiatry

Volume 59, Issue 9, 1 May 2006, Pages 821-828
Biological Psychiatry

Original article
Acute Occupancy of Brain Serotonin Transporter by Sertraline as Measured by [11C]DASB and Positron Emission Tomography

https://doi.org/10.1016/j.biopsych.2005.08.010Get rights and content

Background

In vivo determination of serotonin transporter (5-HTT) occupancy by selective serotonin reuptake inhibitors (SSRI) using positron emission tomography (PET) can aid in determination of dosing. Previous studies used chronic SSRI administration that may down-regulate 5-HTT and used the cerebellum as reference region despite measurable 5-HTT. We examine the reference region and occupancy after acute sertraline dosing.

Methods

We conducted autoradiography of human postmortem cerebellum to determine an optimal reference region. We quantified 5-HTT binding using [11C]DASB and arterial input functions in 17 healthy volunteers. Baseline PET scans were followed by a scan 4–6 days after 25 mg to 100mg of daily sertraline. Several modeling methods and outcome measures were assessed.

Results

Cerebellar gray matter is the optimal reference region. Occupation of 5-HTT sites saturates at low plasma sertraline levels (KD = 1.9 ng/ml) with maximal occupancies of 106.8 ± 8.3% across all brain regions. There is a weak correlation between oral sertraline and plasma sertraline. Occupancy measures vary based on the reference region and outcome measure used.

Conclusions

Occupancy studies and postmortem autoradiography can help define the optimal reference region. Reference tissue modeling using the optimal reference region returns the same occupancy measures as those determined using an arterial input function.

Section snippets

Subjects

Inclusion criteria were assessed through history, Structured Clinical Interview for DSM IV (First 1997), review of systems, physical examination, routine blood tests, pregnancy test, urine toxicology and EKG. Inclusion criteria included: 1) age 18 to 65 years; 2) no Axis I DSM-IV diagnoses; 3) absence of any psychotropic medications for at least 2 weeks; 4) absence of lifetime history of alcohol or substance abuse or dependence; 5) absence of life-time exposure to

Determination of a Reference Region

Due to low but measurable 5-HTT binding in the cerebellum (Kent et al 2002, Kretzschmar et al 2003, Szabo et al 2002), we examined a human cerebellum using [3H]cyanoimipramine autoradiography to suggest the best location to sample in order to minimize specific binding (Figure 1). Specific 5-HTT binding is much higher in the cerebellar vermis (CV, 8.4 fmol/mg) compared with cerebellar gray matter (CG, 1.25 fmol/mg), and cerebellar white matter (CW, .23 fmol/mg).

In in vivo brain imaging studies,

Discussion

Previous in vivo measures of 5-HTT occupancy have reported occupancy of 5-HTT after chronic SSRI intake (Meyer et al 2001, Meyer et al 2004). As we have several methodological differences with these publications, in order to compare our results we analyzed our data as close to possible as was done previously. We apply the graphical approach using CT instead of CG from each scan as the reference region in calculating BP2. With these modifications, we found a lesser degree of occupancy. For

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