Alexander Holik | Medical University of Vienna (original) (raw)
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a r t i c l e i n f o Area-specific and stimulation-dependent changes of human brain activation b... more a r t i c l e i n f o Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the am...
Eur Neuropsychopharmacol, 2009
International Clinical Psychopharmacology, 2009
Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than cital... more Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, highaffinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.
European Neuropsychopharmacology, 2005
![Research paper thumbnail of In vivo imaging of serotonin transporter occupancy by means of SPECT and [ 123 I]ADAM in healthy subjects administered different doses of escitalopram or citalopram](https://attachments.academia-assets.com/48329783/thumbnails/1.jpg)
](Psychopharmacology, 2006
Background Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment ... more Background Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [ 123 I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram. Methods Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [ 123 I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3") for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An E max model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test-retest variability. Results Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60±6, 64±6, and 75±5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65±10 and 70±6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. E max was slightly higher after administration of citalopram (84%) than escitalopram (79%). In the test-retest study, a mean SERT "occupancy" of 4% was found after administration of placebo, the intraclass correlation coefficient was 0.92, and the repeatability coefficient was 0.25. Conclusion SPECT and [ 123 I]ADAM were used to investigate SERT occupancies after single doses of escitalopram or citalopram. The test-retest study revealed good reproducibility of SERT quantification. Similar SERT occupancies were found after administration of equal doses (in respect to mg) of escitalopram and citalopram, giving indirect evidence for a fractional blockade of SERT by the inactive R-citalopram.
European Neuropsychopharmacology, 2007
Indications that folate deficiency increases the risk for depression have been obtained from many... more Indications that folate deficiency increases the risk for depression have been obtained from many biochemical
Neuroimage, 2010
Area-specific and stimulation-dependent changes of human brain activation by selective serotonin ... more Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the amygdala, medial frontal gyrus, parahippocampal, fusiform and middle temporal gyri. Post-hoc t-tests revealed decreased BOLD-signal in the right amygdala and left parahippocampal gyrus in both pharmacological conditions, compared to placebo. Escitalopram, compared to citalopram, induced a decrease of BOLD-signal in the medial frontal gyrus and an increase in the right fusiform and left parahippocampal gyri. Drug effects were concentrated in brain regions with dense serotonergic projections. Both escitalopram and citalopram attenuated BOLD-signal in the amygdala and parahippocampal cortex to emotionally significant stimuli compared to control stimuli. We believe that reduced reactivity in the medial frontal gyrus found for escitalopram compared to citalopram administration might explain the response differences between study drugs as demonstrated in previous clinical trials.
Neuroimage, 2010
Previous studies suggest organizing effects of sex hormones on brain structure during early life ... more Previous studies suggest organizing effects of sex hormones on brain structure during early life and puberty, yet little is known about the adult period. The aim of the present study was to elucidate the role of 17βestradiol, progesterone, and testosterone on cortical sex differences in grey matter volume (GM) of the adult human brain. To assess sexual dimorphism, voxel-based morphometry (VBM) was applied on structural magnetic resonance images of 34 healthy, young adult humans (17 women, 17 men, 26.6 ± 5 years) using analyses of covariance. Subsequently, circulating levels of sex hormones were associated with regional GM using linear regression analyses. After adjustment for sex and total GM, significant associations of regional GM and 17β-estradiol were observed in the left inferior frontal gyrus (β = 0.39, p = 0.02). Regional GM was inversely associated with testosterone in the left inferior frontal gyrus (β = −0.16, p = 0.04), and with progesterone in the right temporal pole (β = −0.39, p = 0.008). Our findings indicate that even in young adulthood, sex hormones exert organizing effects on regional GM. This might help to shed further light on the underlying mechanisms of both functional diversities and congruence between female and male brains.
Biological Psychiatry, 2007
Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomogr... more Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.
![Research paper thumbnail of Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [ 123 I]ADAM SPECT study](https://attachments.academia-assets.com/48329780/thumbnails/1.jpg)
](Psychopharmacology, 2007
Objectives Previous studies have investigated the occupancy of the serotonin reuptake transporter... more Objectives Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [123I]ADAM and single photon emission computed tomography (SPECT). Methods Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [123I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. Results At 6 h after the last dose, mean SERT occupancies were 81.5 ± 5.4% (mean±SD) for escitalopram and 64.0 ± 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 ± 12.1% for escitalopram and 49.0 ± 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. Conclusion The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.
European Neuropsychopharmacology, 2008
We genotyped 1771 tag single nucleotide polymorphisms (SNPs) in 45 genes of the glutamate system ... more We genotyped 1771 tag single nucleotide polymorphisms (SNPs) in 45 genes of the glutamate system and 19 tag SNPs of IL28RA using the Illumina Sentrix Human 1 400k BeadChip. 397 hospitalised Caucasian patients suffering from a depressive episode and treated with antidepressant drugs were evaluated weekly for depression severity using the Hamilton Depression Rating Scale (HDRS) during six weeks. Antidepressant treatment was according to doctors' choice. The severity of suicidal ideation was measured by item three on the HRDS. The main outcome measure was treatment emergent suicidal ideation (TESI), as defined by an increase of suicidal thoughts anytime during hospitalisation (up to 12 weeks) in patients without suicidal thoughts at hospital admission (N = 111).
a r t i c l e i n f o Area-specific and stimulation-dependent changes of human brain activation b... more a r t i c l e i n f o Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the am...
Eur Neuropsychopharmacol, 2009
International Clinical Psychopharmacology, 2009
Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than cital... more Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, highaffinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.
European Neuropsychopharmacology, 2005
Psychopharmacology, 2006
Background Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment ... more Background Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [ 123 I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram. Methods Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [ 123 I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3") for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An E max model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test-retest variability. Results Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60±6, 64±6, and 75±5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65±10 and 70±6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. E max was slightly higher after administration of citalopram (84%) than escitalopram (79%). In the test-retest study, a mean SERT "occupancy" of 4% was found after administration of placebo, the intraclass correlation coefficient was 0.92, and the repeatability coefficient was 0.25. Conclusion SPECT and [ 123 I]ADAM were used to investigate SERT occupancies after single doses of escitalopram or citalopram. The test-retest study revealed good reproducibility of SERT quantification. Similar SERT occupancies were found after administration of equal doses (in respect to mg) of escitalopram and citalopram, giving indirect evidence for a fractional blockade of SERT by the inactive R-citalopram.
European Neuropsychopharmacology, 2007
Indications that folate deficiency increases the risk for depression have been obtained from many... more Indications that folate deficiency increases the risk for depression have been obtained from many biochemical
Neuroimage, 2010
Area-specific and stimulation-dependent changes of human brain activation by selective serotonin ... more Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the amygdala, medial frontal gyrus, parahippocampal, fusiform and middle temporal gyri. Post-hoc t-tests revealed decreased BOLD-signal in the right amygdala and left parahippocampal gyrus in both pharmacological conditions, compared to placebo. Escitalopram, compared to citalopram, induced a decrease of BOLD-signal in the medial frontal gyrus and an increase in the right fusiform and left parahippocampal gyri. Drug effects were concentrated in brain regions with dense serotonergic projections. Both escitalopram and citalopram attenuated BOLD-signal in the amygdala and parahippocampal cortex to emotionally significant stimuli compared to control stimuli. We believe that reduced reactivity in the medial frontal gyrus found for escitalopram compared to citalopram administration might explain the response differences between study drugs as demonstrated in previous clinical trials.
Neuroimage, 2010
Previous studies suggest organizing effects of sex hormones on brain structure during early life ... more Previous studies suggest organizing effects of sex hormones on brain structure during early life and puberty, yet little is known about the adult period. The aim of the present study was to elucidate the role of 17βestradiol, progesterone, and testosterone on cortical sex differences in grey matter volume (GM) of the adult human brain. To assess sexual dimorphism, voxel-based morphometry (VBM) was applied on structural magnetic resonance images of 34 healthy, young adult humans (17 women, 17 men, 26.6 ± 5 years) using analyses of covariance. Subsequently, circulating levels of sex hormones were associated with regional GM using linear regression analyses. After adjustment for sex and total GM, significant associations of regional GM and 17β-estradiol were observed in the left inferior frontal gyrus (β = 0.39, p = 0.02). Regional GM was inversely associated with testosterone in the left inferior frontal gyrus (β = −0.16, p = 0.04), and with progesterone in the right temporal pole (β = −0.39, p = 0.008). Our findings indicate that even in young adulthood, sex hormones exert organizing effects on regional GM. This might help to shed further light on the underlying mechanisms of both functional diversities and congruence between female and male brains.
Biological Psychiatry, 2007
Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomogr... more Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.
Psychopharmacology, 2007
Objectives Previous studies have investigated the occupancy of the serotonin reuptake transporter... more Objectives Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [123I]ADAM and single photon emission computed tomography (SPECT). Methods Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [123I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. Results At 6 h after the last dose, mean SERT occupancies were 81.5 ± 5.4% (mean±SD) for escitalopram and 64.0 ± 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 ± 12.1% for escitalopram and 49.0 ± 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. Conclusion The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.
European Neuropsychopharmacology, 2008
We genotyped 1771 tag single nucleotide polymorphisms (SNPs) in 45 genes of the glutamate system ... more We genotyped 1771 tag single nucleotide polymorphisms (SNPs) in 45 genes of the glutamate system and 19 tag SNPs of IL28RA using the Illumina Sentrix Human 1 400k BeadChip. 397 hospitalised Caucasian patients suffering from a depressive episode and treated with antidepressant drugs were evaluated weekly for depression severity using the Hamilton Depression Rating Scale (HDRS) during six weeks. Antidepressant treatment was according to doctors' choice. The severity of suicidal ideation was measured by item three on the HRDS. The main outcome measure was treatment emergent suicidal ideation (TESI), as defined by an increase of suicidal thoughts anytime during hospitalisation (up to 12 weeks) in patients without suicidal thoughts at hospital admission (N = 111).