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Plasma citalopram concentrations and hormonal responses in 12 volunteers tested twice, under placebo or under intravenous citalopram (7.5 mg over 7.5 min) in a crossover design. a Mean±SEM plasma citalopram levels following citalopram infusion. b Mean±SEM plasma cortisol measured as a change from baseline (time=zero). Mean±SEM plasma prolactin measured as a change from baseline (time=zero)
Source publication
Serotonin (5-hydroxytryptamine, 5-HT) is implicated in the aetiology and treatment of a variety of psychiatric disorders. A limitation of research has been the necessity to use indirect measures of 5-HT function.
We describe a method of analysing pharmacoMRI data using SPM and apply it to the direct i.v. infusion of selective 5-HT reuptake inhibito...
Contexts in source publication
Context 1
... citalopram plasma levels increased, as shown in Fig. 2a. Peak concentrations occurred at 15 min post-infusion with the plasma level reducing after 30 min then plateauing for the subsequent 2 h. ...
Context 2
... increased hormone secretion, as shown in Fig. 2b and c, with a significant interaction between group and time in cortisol response [F(3.78, 41.63)=6.99; p<0.001]. There was a significant difference between conditions in the prolactin response [F(1.00, 58.78)=7.59; p=0.019] with prolactin levels being consistently higher under the infusion drug condition than under placebo from 15 min ...
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Citations
... Some studies indicate that ADs may influence emotional processing in healthy individuals by increasing recognition and recall of positive emotions and reducing salience of negative affects (Harmer et al., 2003a;Harmer et al., 2004). Indeed, ADs were found to attenuate the activity of subcortical limbic neural regions during exposition to negative emotional stimuli (Bigos et al., 2008;Del-Ben et al., 2005;Harmer et al., 2006;McKie et al., 2005;Takahashi et al., 2005). A study evaluated participants' ability to correctly detect subtle expressions of sadness and the results showed that duloxetine (SNRI) might reduce accurate recognition of sadness (Bamford et al., 2015). ...
Pharmacological neuroenhancement refers to the non-medical use of prescription drugs, alcohol, illegal drugs, or the so-called soft enhancers for the purpose of improving cognition, mood, pro-social behavior, or work and academic performance. This phenomenon is undoubtedly more frequent than previously supposed especially amongst university students. The aim of the present paper was to carefully review and comment on the available literature on neuroenhancement, according to Prisma guidelines. The results showed a great use of all prescribed drugs (benzodiazepines, antidepressants, antipsychotics, nootropic compounds, and especially stimulants) as neuroenhancers amongst healthy subjects, although probably the real prevalence is underestimated. The use of illicit drugs and soft enhancers is similarly quite common. Data on the improvement of cognition by other compounds, such as oxytocin and pheromones, or non-pharmacological techniques, specifically deep brain stimulation and transcranial magnetic stimulation, are still limited. In any case, if it is true that human beings are embedded by the desire to overcome the limits of their intrinsic nature, neuroenhancement practices put into question the concept of authenticity. Therefore, the problem appears quite complex and requires to be deepened and analyzed with no prejudice, although within an ethical conceptual frame.
... Functional MRI data collected during an acute citalopram challenge showed that increased SE availability was associated with an increase in the hemodynamic response in the striatum and thalamus. 24 These data provide the context to interpret the observed association between thalamic metabolism and SE innervation, thus expanding the findings in the aforementioned studies also to PD and suggesting that the reported associations between SE and PD symptomatology may be affected by the impact of SE innervation on the thalamus. Although this hypothesis needs to be further explored, it is worthwhile to point out that this interpretation is in line with the reported association of tremor (ie, one of the motor symptoms more often associated with SE dysfunction in PD) 25 and thalamic abnormalities. ...
Background:
Degeneration of the nigrostriatal dopaminergic (DA) and the raphe-thalamic serotonergic (SE) systems is among the earliest changes observed in Parkinson's disease (PD). The consequences of those changes on brain metabolism, especially regarding their impact on the cortex, are poorly understood.
Objectives:
Using multi-tracer molecular imaging, we assessed in a cohort of drug-naive PD patients the association between cortical metabolism and DA and SE system deafferentation of either striatum or thalamus, and we explored whether this association was mediated by either striatum or thalamus metabolism.
Methods:
We recruited 96 drug-naive PD patients (aged 71.9 ± 7.5 years) who underwent [123 I]ioflupane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) and brain [18 F]fluorodeoxyglucose positron emission tomography ([18 F]FDG-PET). We used a voxel-wise analysis of [18 F]FDG-PET images to correlate regional metabolism with striatal DA and thalamic SE innervation as assessed using [123 I]FP-CIT-SPECT.
Results:
We found that [123 I]FP-CIT specific to nondisplaceable binding ratio (SBR) and glucose metabolism positively correlated with one another in the deep gray matter (thalamus: P = 0.001, r = 0.541; caudate P = 0.001, r = 0.331; putamen P = 0.001, r = 0.423). We then observed a direct correlation between temporoparietal metabolism and caudate DA innervation, as well as a direct correlation between prefrontal metabolism and thalamus SE innervation. The effect of caudate [123 I]FP-CIT SBR values on temporoparietal metabolism was mediated by caudate metabolic values (percentage mediated: 89%, P-value = 0.008), and the effect of thalamus [123 I]FP-CIT SBR values on prefrontal metabolism was fully mediated by thalamus metabolic values (P < 0.001).
Conclusions:
These data suggest that the impact of deep gray matter monoaminergic deafferentation on cortical function is mediated by striatal and thalamic metabolism in drug-naive PD. © 2021 International Parkinson and Movement Disorder Society.
... diluted in 8 mL saline or placebo (saline only) was carried out over 8 minutes using a constant infusion after the baseline scan was acquired. Dosage and timing of citalopram administration were chosen to approximate a previous study investigating citalopram effects (McKie et al., 2005). Another scan was performed 50 minutes after the drug challenge. ...
... administered SSRI citalopram on the WM in depressed patients and healthy controls. The dosage of 8 mg was chosen based on a previous study to minimize the occurrence of side effects that might impair the interpretation of results (McKie et al., 2005). While prior studies demonstrated good tolerability, higher dosages entail the risk of side effects such as nausea (Kapitany et al., 1999). ...
... While elevated serotonin levels have been predominantly associated with dendritic spine formation (Ampuero et al., 2010), SSRIs may further elicit changes in axonal quantity, including branching, sprouting, and pruning as well as alterations in axonal density, size, and diameter (Zatorre et al., 2012;Beaulieu, 2014). However, as these processes are rather observed after long-term SSRI administration, other physiological influences, such as axonal swelling (Costa et al., 2018), protein transport (De Vos et al., 2008), or alterations in vascularity (McKie et al., 2005), seem to be more likely to contribute to the observed acute decreases in diffusivity. Recently, it has been shown that even 1 hour of neurofeedback training can induce alterations in WM microstructure and diffusivity parameters (Marins et al., 2019). ...
Background:
Selective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder (MDD). These antidepressants exert their effects by blocking the serotonin transporter (SERT) leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain's WM microstructure are lacking.
Methods:
In this interventional longitudinal study, 81 subjects were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging (DWI) on two separate days receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were calculated within FSL and analysed using tract-based spatial statistics (TBSS).
Results:
The repeated measures ANOVA model revealed significant decreases after SSRI administration in MD, AD and RD regardless of the group (p<0.05, FWE-corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found and no changes in FA were present.
Conclusions:
Our investigation provides first evidence that fast WM microstructure adaptions within one hour after intravenous SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy. This study was registered at clinicaltrials.gov with the identifier NCT02711215.
... Previous studies have demonstrated that the deficiency of monoaminergic neurotransmitters, such as 5-HT, norepinephrine (NE), and dopamine (DA), aggravates depressive behaviors and can be used as a diagnostic index for depression (Massart et al., 2012;Hamon and Blier, 2013). Serotonin is critical for mood processing and emotional regulation in brain areas such as the amygdala and hippocampus (Hervas et al., 2000;McKie et al., 2005), and may be essential for ameliorating depressive behaviors. Clinically depressed patients reportedly have impaired glutamatergic and hyperactive acetylcholine systems, whereas they have a dramatically suppressed gammaaminobutyric acid (GABA) system (Pytka et al., 2016;Murrough et al., 2017). ...
Depression has emerged as a major cause of mortality globally. Many studies have reported risk factors and mechanisms associated with depression, but it is as yet unclear how these findings can be applied to the treatment and prevention of this disorder. The onset and recurrence of depression have been linked to diverse metabolic factors, including hyperglycemia, dyslipidemia, and insulin resistance. Recent studies have suggested that depression is accompanied by memory loss as well as depressive mood. Thus, many researchers have highlighted the relationship between depressive behavior and metabolic alterations from various perspectives. Glucagon-like peptide-1 (GLP-1), which is secreted from gut cells and hindbrain areas, has been studied in metabolic diseases such as obesity and diabetes, and was shown to control glucose metabolism and insulin resistance. Recently, GLP-1 was highlighted as a regulator of diverse pathways, but its potential as the therapeutic target of depressive disorder was not described comprehensively. Therefore, in this review, we focused on the potential of GLP-1 modulation in depression.
... We used SPM12 software to realign the different sets of data, enabling statistical comparisons between the different doses of ATX and saline injection. Time-bins comparisons were performed, similarly to pharmacological MRI protocols (McKie et al., 2005;Vidal et al., 2019) and provided high-resolution mapping of CBV changes following ATX injection that was consistent with results of the ROIs analysis. As a further step towards drug characterization, we used ICA to analyze the data without making any assumption on time-bins or temporal regressors. ...
Functional ultrasound (fUS) is a new tool enabling the imaging of brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics. This innovative technique has not yet demonstrated its full potential in pharmacological applications and drug development. In the current proof-of-concept study, the impact of atomoxetine (ATX), a potent norepinephrine reuptake inhibitor and non-stimulant treatment marketed in attention-deficit/hyperactivity-disorder, was evaluated in anesthetized rat using pharmacological functional ultrasound (pharmaco-fUS) at increasing doses (0.3, 1 and 3 mg/kg). Using regions of interest (acute changes of CBV and functional connectivity) or pixel-based (general linear modeling and independent component analysis) analysis, we here demonstrated that ATX consistently displayed a hemodynamic effect in the visual cortex, the dentate gyrus and thalamus, especially visual areas such as lateral posterior thalamic nuclei and lateral geniculate nuclei (LGN). The time profile of ATX effects was dose-dependent, with fastest CBV increases at the highest dose, and longer CBV increases at the intermediate dose. Standardizing the use of pharmaco-fUS could improve our understanding of the mechanism of action of drugs active in the brain and might constitute a step to move forwards new drugs to development in neurological disorders.
... Following these procedures, an intravenous line was placed and all subjects underwent the phMRI scan. During the phMRI scan, a bolus of 7.5 mg citalopram (dissolved in 45 ml saline) was infused over 7.5 minutes, followed by 15 ml saline flush over 2.5 minutes, similar to a previous study (McKie et al., 2005). ...
... In contrast to the studies mentioned above, most preclinical studies, and one clinical study that also used BOLD signal measurements, reported an increased activation following an SSRI challenge (Bouet et al., 2012;Klomp et al., 2012b;McKie et al., 2005;Schwarz et al., 2007). This is interesting, as typically a positive linear correlation between CBF and BOLD signal is found, mainly during (cognitive) task activation (Raichle et al., 1976;Sokoloff, 1981). ...
... The change in MRI signal as a response to a 5-HT challenge is known to be directly influenced by extracellular 5-HT levels (Preece et al., 2009), and indirectly by binding of 5-HT to its receptors (Sekar et al., 2011), and lastly by neurotransmitter release per se (Logothetis and Wandell, 2004). Together, these factors might explain the reported increase in BOLD signal following SSRI treatment (Bouet et al., 2012;Klomp et al., 2012b;McKie et al., 2005;Schwarz et al., 2007), whereas decreases in ASL signal are reported in other studies (Chen et al., 2011;Kaichi et al., 2016;Klomp et al., 2012a;Windischberger et al., 2010). Hence, future research would benefit from measures that can distinguish between neuronal activation and vascular effects. ...
Preclinical studies have demonstrated that antidepressant treatment in juvenile rodents affect the ontogeny of the serotonin system. However, whether early antidepressant use has similar effects on the development of the serotonin system in humans remains unknown. Therefore, we investigated whether effects of selective serotonin reuptake inhibitor (SSRI) treatment on the serotonin system are modulated by age. With pharmacological Magnetic Resonance Imaging the cerebral blood flow (CBF) response to an acute citalopram challenge was measured, as a proxy for serotonin function. Fifty-one females with major depressive disorder or anxiety disorder were stratified into three groups: 1) those treated with SSRIs <23 years of age, 2) those treated with SSRIs >23 years of age, and 3) those that were never treated with SSRIs. Additionally, a group of 14 healthy controls was included. CBF decreased after a citalopram challenge in the amygdala, hippocampus and orbitofrontal cortex across the whole sample. However, in contrast to preclinical studies, we did not find any age-dependent effect of SSRI exposure on the CBF response. In view of recent concerns on potential adverse effects of SSRIs administered to children, future studies are needed to replicate our negative findings in larger samples sizes and potentially in a prospective design.
... Therefore, the BOLD patterns observed in our study could be due to indirect effects on other neurons than those expressing 5-HT 1A receptors. This must be kept in mind when interpreting the results, especially because 5-HT 1A autoreceptors can modulate endogenous serotonin release, which is likely to modify BOLD signal in serotonergic projection areas (Preece et al., 2009;McKie et al., 2005;Jenkins, 2012). Furthermore, 5-HT 1A agonists might have peripheral effects on the vascular tone that would impact the BOLD signal, also the effect of 5-HT 1A receptor stimulation on blood vessels is not clearly characterized. ...
The emerging concept of "biased agonism" denotes the phenomenon whereby agonists can preferentially direct receptor signalling to specific intracellular responses among the different transduction pathways, thus potentially avoiding side effects and improving therapeutic effects. The aim of this study was to investigate biased agonism by using pharmacological magnetic resonance imaging (phMRI). The cerebral blood oxygen level dependent (BOLD) signal changes induced by increasing doses of two serotonin 5-HT1A receptor biased agonists, NLX-112 and NLX-101, were mapped in anaesthetized rats. Although both compounds display high affinity, selectivity and agonist efficacy for 5-HT1A receptors, NLX-101 is known to preferentially activate post-synaptic receptors, whereas NLX-112 targets both pre- and post-synaptic receptors. We used several doses of agonists in order to determine if the regional selectivity of NLX-101 was dose-dependent. NLX-112 and NLX-101 induced different positive and negative hemodynamic changes patterns at equal doses. Importantly, NLX-101 had no significant effect in regions expressing pre-synaptic receptors contrary to NLX-112. NLX-112 also produced higher BOLD changes than NLX-101 in the orbital cortex, the somatosensory cortex, and the magnocellular preoptic nuclei. In other regions such as the retrosplenial cortex and the dorsal thalamus, the drugs had similar effects. In terms of functional connectivity, NLX-112 induced more widespread changes than NLX-101. The present phMRI study demonstrates that two closely-related agonists display notable differences in their hemodynamic "fingerprints". These data support the concept of biased agonism at 5-HT1A receptors and raise the prospect of identifying novel therapeutics which exhibit improved targeting of brain regions implicated in neuropsychiatric disorders.
... The change in SERT binding between SPECT-1 and SPECT-2 was used to calculate SERT occupancy. Then, phMRI was performed, in which all participants received a 7.5 mg intravenous challenge with citalopram in line with previous studies (McKie et al., 2005;Schouw et al., 2012). This intravenous dose was intended to induce saturated occupancy in all groups, regardless of oral dose. ...
... For example, administration of both the SSRIs fluoxetine (Klomp et al., 2012b) and citalopram (Sekar et al., 2011) elicited increased BOLD responses in rats. In humans, citalopram i.v. also increased the BOLD response in the striatum, amygdala, hippocampus and thalamus (McKie et al., 2005). In contrast, data from studies using ASL and PET imaging suggest that thalamic CBF and metabolism are actually decreased after intravenous SSRI administration (Geday et al., 2005;Schouw et al., 2012). ...
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.
... Current applications have already demonstrated great insight into the association between brain response and neurotransmitter system actions specific to pharmacological effects. These include studies of amphetamine and SSRIs in rodents (Schwarz et al., 2007) as well as human investigations of SSRIs (McKie et al., 2005) and ketamine (Deakin et al., 2008). The latter has also received particular interest due to its rapid antidepressant effects (Zarate et al., 2006) with models derived from previous data (De Simoni et al., 2013) or directly from ketamine plasma levels . ...
In addition to the assessment of local alterations of specific brain regions, the investigation of entire networks with in vivo neuroimaging techniques has gained increasing attention. In general, connectivity analysis refers to the investigation of links between brain regions, with the aim to characterize their interactions and information transfer. These may represent or relate to different physiological characteristics (structural, functional, or metabolic information) and can be calculated across different levels of granularity (2 regions vs whole brain). In this article, we provide an overview of different connectivity analysis approaches with interpretations and limitations as well as examples in pharmacological imaging and clinical applications. Structural connectivity obtained from diffusion MRI enables the reconstruction of neuronal fiber tracts. These physical links represent major constraints of functional connections, which are in turn defined as correlations between signal time courses. In addition, molecular connectivity approaches based on PET imaging enable the assessment of interregional associations of metabolic demands and neurotransmitter systems. Application of these approaches in clinical investigations has demonstrated novel alterations in various neurological and psychiatric disorders on a network level. Future work should aim for the combined assessment of multiple imaging modalities and to establish robust biomarkers for clinical use. These advancements will further improve the biological interpretation of connectivity metrics and networks of the human brain.
... These included the widely used models of drug plasma concentrations and infusion timing, as well as a novel approach which employs the simultaneously measured time course of serotonin transporter binding. The randomized, double-blind placebo-controlled study design and drug challenge paradigm were approximated to a pioneering phMRI study of citalopram effects ( McKie et al., 2005 ). This study has first introduced a model-free analysis method which relies on separating phMRI data into time bins and comparing the deviations from baseline between placebo and drug challenge scans. ...
... A widely used model-free approach to the detection of phMRI response was applied with minimal necessary modifications in order to provide the most accurate replication ( McKie et al., 2005 ). To this end, fMRI resting-was separated into twelve 2 min time bins acquired during and after SSRI infusion. ...
... No significant differences in deviation from baseline between SSRI and placebo scans could be shown for any time bin recorded after start of drug challenge. As the results of the first application of this method in the literature were described at an uncorrected significance level of p < 0.001 ( McKie et al., 2005 ), uncorrected results were also inspected. In this manner, from the first time bin recorded after start of challenge onwards, widely scattered differences were seen between conditions which were not consistent between time bins. ...
