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Randomized Controlled Trial
. 2019 Jun;33(6):660-669.
doi: 10.1177/0269881119836229. Epub 2019 Mar 19.

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study

Anouk Schrantee  1   2 , Michelle M Solleveld  1   2 , Hilde Schwantje  1 , Willem B Bruin  3 , Henk-Jan Mm Mutsaerts  1 , Sofie M Adriaanse  1 , Paul Lucassen  2 , Jan Booij  1 , Liesbeth Reneman  1
Affiliations
Randomized Controlled Trial

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study

Anouk Schrantee et al. J Psychopharmacol. 2019 Jun.

Abstract

Background: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects.

Aims: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT).

Methods: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region).

Results: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change.

Conclusion: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

Keywords: Citalopram; SPECT; phMRI; serotonin.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Study day. SPECT: single photon emission computed tomography; phMRI: pharmacological magnetic resonance imaging; iv: intravenous
Figure 2.
Figure 2.
Single photon emission computed tomography (SPECT) and arterial spin labelling regions of interest. (a) Representative T1-weighted image with co-registered SPECT data (red/yellow) and the individual thalamic mask (green) superimposed. (b) Representative cerebral blood flow (CBF) image masked by the individual grey matter mask with the individual thalamic mask (green) and occipital mask (red) superimposed.
Figure 3.
Figure 3.
Subjective ratings. Line graphs of subjective ratings over the four time points for each group separately. SPECT: single photon emission computed tomography; phMRI: pharmacological magnetic resonance imaging; iv: intravenous
Figure 4.
Figure 4.
Blood plasma levels. Blood samples were collected before the second single photon emission computed tomography (SPECT) scan and after the pharmacological magnetic resonance imaging (phMRI) scan. Citalopram plasma levels (μg/L) were determined using mass spectrometry. (a) Citalopram plasma levels prior to SPECT 2 at 3 h post-oral-citalopram. (b) Citalopram plasma levels after the phMRI scan at 30 min post-iv- citalopram on a log scale. *Analysis of variance: p<0.05 iv: intravenous
Figure 5.
Figure 5.
Single photon emission computed tomography (SPECT) and pharmacological magnetic resonance imaging (phMRI) results. (a) Scatter dot plots of the thalamic binding potential (BPND) for each group for SPECT 2, and (b) the difference in thalamic BPND, normalized to the placebo group, from pre- to post-oral citalopram for each group. (c) Estimated marginal mean with 95% confidence interval of thalamic cerebral blood flow (CBF) (corrected for baseline thalamic CBF) for each group from pre- to post-intravenous citalopram, and (d) of occipital CBF (corrected for baseline occipital CBF). *Analysis of variance: p<0.05
Figure 6.
Figure 6.
Arterial spin labelling (ASL) data quality. Left: a representative cerebral blood flow (CBF) map of one subject for a 5-min ASL acquisition. Centre: the mean CBF map averaged over all subjects. Right: the mean temporal signal to noise ratio (tSNR) map averaged over all subjects. All maps are masked with a grey matter mask (>25% probability of being grey matter) and overlaid on the mean T1 image of all subjects.
Figure 7.
Figure 7.
Cardiovascular effects. (a) Heart rate (HR) was measured during the arterial spin labelling (ASL) scan session. Pre- and post-intravenous citalopram averages (over the same 5 min over which the cerebral blood flow was calculated) are shown in beats per minute. (b) 2D-flow was measured just before and straight after the ASL scan. Pre- and post-blood flow to the brain in the intracranial arteries is shown in mL/s. Data represent mean ± standard error of the mean.
Figure 8.
Figure 8.
Correlation plots. (a) Correlation plot between citalopram plasma levels (μg/L) and thalamic binding potential (ΔBPND). (b) Partial correlation plot between citalopram plasma levels (μg/L) and thalamic ΔCBF (taking into account the baseline thalamic cerebral blood flow (CBF)). (c) Partial correlation plot between thalamic ΔBPND and thalamic ΔCBF (taking into account the baseline thalamic CBF).
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