Selective Serotonin Reuptake Inhibitor Citalopram Research Articles

A comparative analysis of selective serotonin reuptake inhibitors and fall risk in older adults.

One in five older adults (age 65+) uses an antidepressant medication. However, little is known about how fall risk differs between commonly prescribed medications. We examine the comparative association between individual selective serotonin reuptake inhibitors (SSRI) and self-reported falls in older adults. We used data from 2010-2017 Medicare Current Beneficiary Surveys, a nationally representative survey of Medicare beneficiaries. We included participants from three different panels surveyed over two successive years. Participants were limited to community-dwelling Medicare beneficiaries 65+, enrolled in Medicare Part D, and taking an SSRI (n=1023) during baseline years. Participants were asked about demographic and health characteristics, medication use (including dose, frequency, duration of use) and self-reported falls as any fall or recurrent falls in the past year. We compared individual SSRI (citalopram or escitalopram vs sertraline) use by the average monthly total standardized daily dose (TSDD) and self-reported falling, controlling for potential confounders. Descriptive analysis and multivariable logistic regressions were conducted using SAS-callable SUDAAN. Citalopram/escitalopram (n=460 users; 45.0% of all SSRI users) and sertraline (n=294 users; 28.7% of all SSRI users) were the most commonly prescribed SSRIs. Overall, 36.3% of citalopram/escitalopram users and 39.4% of sertraline users reported a fall in the year following medication use. There were no statistically significant differences between sertraline and citalopram/escitalopram users of either low or medium TSDD levels in the risk of self-reported any or recurrent falls. However, users of high TSDD of sertraline (>75 mg) had a lower risk of recurrent falls compared to high TSDD citalopram (>30 mg) or escitalopram (>15 mg) daily for 30 days. These findings suggest a potential comparative safety benefit of sertraline compared to citalopram/escitalopram at high doses related to recurrent falls. Additional comparative studies of individual antidepressants may better inform fall risk management and prescribing for older adults.

Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways

ABSTRACT Objectives To evaluate the effects of modafinil on neuropathic pain induced by sciatic nerve cuffing in mice, and possible contribution of nitrergic/inflammatory and serotonergic systems. Methods Neuropathic pain was induced by applying a polyethylene cuff around the left sciatic nerve. Seven days later, mice received modafinil (50, 100, and 200 mg/kg; intraperitoneal [i.p.]) and morphine (10 mg/kg, i.p.) as control. Mice also received pretreatments of the nonselective nitric oxide (NO) synthase (NOS) inhibitor L-NAME, the selective neuronal NOS inhibitor 7-nitroindazole, the selective inducible NOS inhibitor aminoguanidine, and the selective serotonin reuptake inhibitor citalopram before modafinil (100 mg/kg). von Frey test was used to evaluate mechanical allodynia. Additionally, sciatic nerves were collected for histopathological analysis. Tissue levels of NO metabolites, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were assessed. Results Animals whose sciatic nerves were cuffed had a significantly (P<0.001) decreased paw withdrawal threshold (PWT) compared with the sham-operated group. Modafinil (100 mg/kg) and morphine significantly reversed PWT (P<0.001). Pretreatments with L-NAME, 7-nitroindazole, aminoguanidine, and citalopram in different groups markedly reversed analgesic effects of modafinil. Tissue homogenates of Cuffed sciatic nerves showed significantly higher levels of NO metabolites, TNF-α and IL-6 (P<0.001). Modafinil lowered NO metabolites, TNF-α, and IL-6 levels (P<0.001). Histopathology illustrated marked axonal degeneration and shrinkage in the cuffed sciatic nerve, which were improved in the modafinil-treated group. Conclusions Modafinil exerts analgesic and neuroprotective effects in cuff-induced neuropathic mice via possible involvement of the nitrergic/inflammatory and serotonergic systems.

Citalopram for treatment of cocaine use disorder: A Bayesian drop-the-loser randomized clinical trial

BackgroundMedication development research for cocaine use disorder (CUD) has been a longstanding goal in addiction research, but has not resulted in an FDA-approved treatment. Rising cocaine use rates underscore the need for efficient adaptive designs. This study compared differences between two doses of the selective serotonin reuptake inhibitor (SSRI) citalopram (versus placebo) on duration of cocaine abstinence and applied adaptive decision rules to select the ‘best efficacy’ dose. MethodsA double-blind, placebo-controlled, randomized Bayesian drop-the-loser (DTL) trial with three arms compared placebo to citalopram 20 mg and 40 mg. Adults (N = 107) with CUD attended thrice-weekly clinic visits for 9 weeks. The primary outcome was longest duration of abstinence (LDA), based on continuous cocaine-negative urine drug screens (UDS). The secondary outcome was probability of cocaine-negative UDS during treatment. A planned interim analysis performed at approximately 50% of recruitment dropped the least-effective active medication. Bayesian inference was used for all analyses with a pre-specified posterior probability (PP) threshold PP ≥ 95% considered statistically reliable evidence ResultsCitalopram 40 mg satisfied interim efficacy criteria and was retained for the second half of the trial. For LDA, analyses indicated PP = 82% and PP = 65% of benefit for 40 mg and 20 mg, respectively (each relative to placebo). The odds of having cocaine-negative UDS decreased in all groups over 9 weeks but remained higher for 40 mg (PP = 97.4%) ConclusionsNeither dose met the 95% PP threshold for the primary outcome; however, 40 mg provided moderate-to-strong evidence for positive effects on LDA and cocaine-negative UDS. The 40 mg dose was declared the “winner” in this DTL trial.

Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes

BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, primarily consisting of severe and persistent thrombocytopenia. We hypothesize that this is caused by selective uptake of MIBG via the serotonin transporter (SERT) located on platelets and megakaryocytes. In this study, we have investigated whether in vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG and whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent this radiotoxic MIBG uptake.MethodsPeripheral blood CD34+ cells were differentiated to human megakaryocytic cells using a standardized culture protocol. Prior to [3H]serotonin and [125I]MIBG uptake experiments, the differentiation status of megakaryocyte cultures was assessed by flow cytometry. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess SERT and NET (norepinephrine transporter) mRNA expression. On day 10 of differentiation, [3H]serotonin and [125I]MIBG uptake assays were conducted. Part of the samples were co-incubated with the SSRI citalopram to assess SERT-specific uptake. HEK293 cells transfected with SERT, NET, and empty vector served as controls.ResultsIn vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG. After 10 days of differentiation, megakaryocytic cell culture batches from three different hematopoietic stem and progenitor cell donors showed on average 9.2 ± 2.4 nmol of MIBG uptake per milligram protein per hour after incubation with 10–7 M MIBG (range: 6.6 ± 1.0 to 11.2 ± 1.0 nmol/mg/h). Co-incubation with the SSRI citalopram led to a significant reduction (30.1%—41.5%) in MIBG uptake, implying SERT-specific uptake of MIBG. A strong correlation between the number of mature megakaryocytes and SERT-specific MIBG uptake was observed.ConclusionOur study demonstrates that human megakaryocytes cultured in vitro are capable of MIBG uptake. Moreover, the SSRI citalopram selectively inhibits MIBG uptake via the serotonin transporter. The concomitant administration of citalopram to neuroblastoma patients during [131I]MIBG therapy might be a promising strategy to prevent the onset of thrombocytopenia.

Perinatal SSRI Exposure Disrupts G Protein-coupled Receptor BAI3 in Developing Dentate Gyrus and Adult Emotional Behavior: Relevance to Psychiatric Disorders

Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed to pregnant women suffering with depression, although the long-term impact of these medications on exposed offspring are poorly understood. Perinatal SSRI exposure alters human offspring’s neurodevelopment and increases risk for psychiatric illness in later life. Rodent studies suggest that perinatal SSRI-induced behavioral abnormalities are driven by changes in the serotonin system as well as epigenetic and transcriptomic changes in the developing hippocampus. A major gene altered by perinatal SSRI exposure is the G-protein coupled receptor Brain Angiogenesis Inhibitor 3 (BAI3). Our present study shows that perinatal exposure to the SSRI citalopram increases mRNA expression of Bai3 and related molecules (including its C1ql ligands) in the early postnatal dentate gyrus of male and female offspring. Transient Bai3 mRNA knockdown in perinatal SSRI-exposed dentate gyrus lessened behavioral consequences of perinatal SSRI exposure, leading to increased active stress coping. To determine translational implications of this work, we examined expression of BAI3 and related molecules in hippocampus and prefrontal cortex from patients that suffered with depression or schizophrenia relative to healthy control subjects. We found sex- and region-specific changes in mRNA expression of BAI3 and its ligands C1QL2 and C1QL3 in men and women with a history of psychiatric disorders compared to healthy controls. Together these results suggest that abnormal BAI3 signaling may contribute to molecular mechanisms that drive adverse effects of perinatal SSRI exposure, and show evidence for alterations of BAI3 signaling in the hippocampus of patients that suffer depression and schizophrenia.

A cross-sectional study of the relationship between CYP2D6 and CYP2C19 variations and depression symptoms, for women taking SSRIs during pregnancy.

Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical guidelines provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; however, they are based on evidence from non-pregnant cohorts. This study aimed to test the hypothesis that women with function-altering variants (increased, decreased, or no function) in these pharmacogenes, taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants are associated with normal SSRI metabolism. Comprehensive CYP2D6 and CYP2C19 genotyping using a range of methods, including gene copy number analysis, was performed as secondary analyses on two longitudinal cohorts of pregnant women (N= 83) taking the SSRIs paroxetine, citalopram, escitalopram, or sertraline. The Kruskal-Wallis test compared mean depression scores across four predicted metabolizer groups: poor (n= 5), intermediate (n= 10), normal (n= 53), and ultrarapid (n= 15). There were no significant differences between mean depression scores across the four metabolizer groups (H(3) = .73, p= .87, eta-squared = .029, epsilon-squared = .0089). This is the first study of the relationship in pregnancy between CYP2C19 pharmacogenetic variations and depression symptoms in the context of SSRI use. Findings from this initial study do not support the clinical use of pharmacogenetic testing for SSRI use during the second or third trimesters of pregnancy, but these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, especially as companies offering direct-to-consumer genetic testing expand their marketing efforts.

A Review on Post-traumatic Stress Disorder (PTSD): Symptoms, Therapies and Recent Case Studies.

Post-traumatic stress disorder (PTSD), previously known as battle fatigue syndrome or shell shock, is a severe mental disturbance condition that is normally triggered by the experience of some frightening/scary events or trauma where a person undergoes some serious physical or mental harm or threatened. PTSD is a long-life effect of the continuous occurrence of traumatic conditions, leading to the production of feelings of helplessness, intense fear, and horror in the person. There are various examples of events that can cause PTSD, such as physical, mental, or sexual assault at home or working place by others, unexpected death of a loved one, an accidental event, war, or some kind of natural disaster. Treatment of PTSD includes the removal or reduction of these emotional feelings or symptoms with the aim to improve the daily life functioning of a person. Problems which are needed to be considered in case of PTSD like ongoing trauma, abusive or bad relationships. Various drugs which are used for the treatment of PTSD include selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluvoxamine, fluoxetine, etc.); tricyclic antidepressants (amitriptyline and isocarboxazid); mood stabilizers (Divalproex and lamotrigine); atypical antipsychotics (aripiprazole and quetiapine), etc. In this review, we have covered the different risk factors, case studies related to various treatment options with different age group of peoples with PTSD and their effects on them. We have also covered the symptoms and associated disorders which can play a key role in the development of PTSD.

Making Sense of Life-History Effects of the Antidepressant Citalopram in the Copepod Nitocra spinipes Using a Bioenergetics Model.

The global consumption of human antidepressants has steadily increased over the last years. The most widely prescribed antidepressants are the selective serotonin reuptake inhibitors (SSRIs), which have been linked to various life-history effects in nontarget organisms. We investigated the effects of the SSRI citalopram hydrobromide on the life history of the copepod Nitocra spinipes. Slight but significant developmental delay effects were observed at nominal concentrations of 0.1 and 1 µg/L, with stronger effects occurring at measured concentrations of 178 µg/L and above. At 77 µg/L and above, a significant increase in adult body length and offspring production/brood was found, although the time between brood releases remained unaffected. The pre-adult surviving fraction was significantly reduced (by 44%) at 765 µg/L. For a mechanistic evaluation of these observations, we used a bioenergetics model for N. spinipes based on the dynamic energy budget theory. Toxicokinetic and toxicodynamic submodels were used to dynamically simulate the chemical uptake and elimination, as well as dose-response relationships for hypothetical physiological modes of action and survival over time. Although none of the commonly invoked physiological modes of action, acting on assimilation, maintenance, growth, or offspring production, could explain the observed combination of effects, a newly proposed physiological mode of action acting on the process of maturation delivered correct predictions in terms of each effect's direction. The model fits could be further improved by allowing for a gentler concentration-effect slope and by adding an auxiliary physiological mode of action acting on the reproduction efficiency. The quantitative explanations provided in the present study offer a starting point for exploratory simulation studies investigating the effects of SSRIs at higher ecological levels. Environ Toxicol Chem 2021;40:1928-1939. © 2021 SETAC.

Selective serotonin reuptake inhibitor citalopram ameliorates cognitive decline and protects against amyloid beta-induced mitochondrial dynamics, biogenesis, autophagy, mitophagy and synaptic toxicities in a mouse model of Alzheimer's disease.

In the current study, we investigated the protective role of citalopram against cognitive decline, impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective autophagy, mitophagy and synaptic dysfunction in APP transgenic mouse model of Alzheimer's disease (ad). We treated 12-month-old wild-type (WT) and age-matched transgenic APP mice with citalopram for 2months. Using Morris Water Maze and rotarod tests, quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed cognitive behavior, RNA and protein levels of mitochondrial dynamics, biogenesis, autophagy, mitophagy, synaptic, ad-related and neurogenesis genes in wild-type and APP mice treated and untreated with citalopram. Citalopram-treated APP mice relative to citalopram-untreated APP mice exhibited improved cognitive behavior. Increased levels of mRNA associated with mitochondrial fission and ad-related genes; decreased levels of fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes were found in APP mice relative to WT mice. However, APP mice treated with citalopram compared to citalopram-untreated APP mice revealed reduced levels of the mitochondrial fission and ad-related genes and increased fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes. Our protein data agree with the mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice; these were reversed in citalopram-treated APP mice. Further, Golgi-cox staining analysis revealed reduced dendritic spines in APP mice relative to WT mice. However, citalopram-treated APP mice showed significantly increased dendritic spines, indicating that citalopram enhances spine density, synaptic activity and improved cognitive function in APP mice. These findings suggest that citalopram reduces cognitive decline, Aβ levels and mitochondrial and synaptic toxicities and may have a strong protective role against mutant APP and Aβ-induced injuries in patients with depression, anxiety and ad.

Sensing serotonin secreted from human serotonergic neurons using aptamer-modified nanopipettes.

The serotonergic system in the human brain modulates several physiological processes, and altered serotonergic neurotransmission has been implicated in the neuropathology of several psychiatric disorders. The study of serotonergic neurotransmission in psychiatry has long been restricted to animal models, but advances in cell reprogramming technology have enabled the generation of serotonergic neurons from patient-induced pluripotent stem cells (iPSCs). While iPSC-derived human serotonergic neurons offer the possibility to study serotonin (5-HT) release and uptake, particularly by 5-HT-modulating drugs such as selective serotonin reuptake inhibitors (SSRIs), a major limitation is the inability to reliably quantify 5-HT secreted from neurons in vitro. Herein, we address this technical gap via a novel sensing technology that couples 5-HT-specific DNA aptamers into nanopores (glass nanopipettes) with orifices of ~10 nm to detect 5-HT in complex neuronal culture medium with higher selectivity, sensitivity, and stability than existing methods. The 5-HT aptamers undergo conformational rearrangement upon target capture and serve as gatekeepers of ionic flux through the nanopipette opening. We generated human serotonergic neurons in vitro and detected secreted 5-HT using aptamer-coated nanopipettes in a low nanomolar range, with the possibility of detecting significantly lower (picomolar) concentrations. Furthermore, as a proof of concept, we treated human serotonergic neurons in vitro with the SSRI citalopram and detected a significant increase in extracellular 5-HT using the aptamer-modified nanopipettes. We demonstrate the utility of such methods for 5-HT detection, raising the possibility of fast quantification of neurotransmitters secreted from patient-derived live neuronal cells.

Biochemical and cellular biomarkers in brown trout (Salmo trutta f. fario) in response to the antidepressants citalopram and venlafaxine

BackgroundDuring the last decades, a worldwide increase in the number of cases of depression accompanied by rising prescription rates of antidepressants was recorded. In Germany, the two most prescribed antidepressants are the selective serotonin reuptake inhibitor (SSRI) citalopram and the serotonin and noradrenalin reuptake inhibitor (SNRI) venlafaxine, taking about 30% of the market share. Both antidepressants are found frequently in surface waters and have the potential of adversely affecting aquatic organisms. Most studies dealing with antidepressants address apical endpoints and behaviour; however, only few studies investigate biochemical biomarkers and histopathological alterations. We conducted citalopram and venlafaxine exposure experiments over 5 months, starting with brown trout eggs in the eyed-ova stage, as well as with juvenile brown trout for 4 weeks. Exposure concentrations ranged from environmentally relevant 1 µg/L up to 1 mg/L. In this study, we investigated the effects of the antidepressants on b-esterase activity (neurotoxicity), stress protein level (proteotoxicity) and superoxide dismutase activity (oxidative stress). Additionally, we assessed the health status of the liver by means of histopathological analyses.ResultsWe were able to show that both antidepressants did neither induce proteotoxic nor neurotoxic effects in brown trout. But for venlafaxine, the biochemical biomarker for oxidative stress (superoxide dismutase activity) was significantly increased in larvae exposed to at least 10-µg/L venlafaxine at 7 °C. With regard to liver histopathology, fish exposed to higher citalopram concentrations were in a worse health condition than control fish irrespective of their life stage. Also, the energy storage of fish exposed to 1 mg/L citalopram was reduced.ConclusionThus, we here report citalopram-dependent histopathological alterations in brown trout liver, and the induction of oxidative stress by venlafaxine.

How often are antidepressants prescribed off-label among older adults in Germany? A claims data analysis.

To estimate the extent of off-label prescribing of antidepressants in older adults and to characterize patients with off-label vs on-label prescriptions of antidepressants using a large German health claims database. Using data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a cross-sectional study in adults aged 65 years or older with a dispensation of an antidepressant between 1 January 2009 and 31 December 2015 after a period of 365 days without such a dispensation. We assessed the overall and annual proportion of off-label prescriptions of antidepressants by class and individual substance. Among 263 276 incident users of antidepressants, the proportion of off-label prescribing was 43.6% (95% CI 43.4-43.8%) with little variation between 2009 and 2015 (42.2-44.4%). The proportion of off-label use was higher in men (49%) than women (41%). While the proportion of off-label prescriptions was highest for tri- and tetracyclic antidepressants with 56.2% (amitriptyline 54.6%, maximum 65.9% for trimipramine), it amounted to 41.8% for selective serotonin reuptake inhibitors (citalopram 41.6%, maximum 46.0% for escitalopram) and was 51.2% for mirtazapine. Indicators of overall morbidity were similar in both groups, eg, pain was coded in 72% of off-label users vs 77% of on-label users (insomnia 20% vs 24%). Our study suggests a high prevalence of off-label antidepressant use among older adults in Germany, which was not restricted to certain classes of antidepressants or individual antidepressants. Given the unclear risk-benefit ratio, studies investigating the safety of off-label use among older adults for individual antidepressants are urgently needed.

Divergent Response to the SSRI Citalopram in Male and Female Three-Spine Sticklebacks (Gasterosteus aculeatus)

Selective serotonin reuptake inhibitors (SSRIs) are psychotropic pharmaceuticals used as antidepressants. SSRIs are commonly found in surface waters in populated areas across the globe. They exert their effect by blocking the serotonin re-uptake transporter in the presynaptic nerve ending. The present study examined whether behavioural effects to exposure to SSRI citalopram depend on personality and sex in the stickleback (Gasterosteus aculeatus). Three aspects of stickleback behaviour are examined: feeding behaviour, aggression, and boldness. We exposed sticklebacks to 350–380 ng/l citalopram for 3 weeks. Feeding and aggressive behaviour were recorded before and after exposure, whereas scototaxis behaviour was tested after exposure. The results show treatment effects in feeding and aggressive behaviour. Feeding is suppressed only in the male group (χ2 = 20.4, P < 0.001) but not in the females (χ2 = 0.91, P = 0.339). Aggressive behaviour was significantly affected by treatment (χ2 = 161.9, P < 0.001), sex (χ2 = 86.3, P < 0.001), and baseline value (χ2 = 58.8, P < 0.001). Aggressiveness was suppressed by citalopram treatment. In addition, the fish showed no change in aggression and feeding behaviour over time regardless of sex and treatment, which indicate personality traits. Only females are affected by treatment in the scototaxis test. The exposed females spent significantly (χ2 = 5.02, P = 0.050) less time in the white zone than the female controls.

Development of a new method for drug detection based on a combination of the dried blood spot method and capillary electrophoresis

The aim of this study was to develop a new approach to sample preparation of biological material based on a combination of the Dried Blood Spot (DBS) method and capillary electrophoresis coupled with mass spectrometry (CE-MS) for the analysis of blood samples collected in vivo or post-mortem. The proposed approach allowed the identification of typical drugs from different groups, such as tricyclic antidepressants (amitriptyline, imipramine), selective serotonin reuptake inhibitors (citalopram), benzodiazepines (tetrazepam) and hypnotics (zolpidem). In this study, a blood sample was spotted on FTA DMPK C cards, then dried, and 6-mm discs were cut out. The sample preparation procedure involved microwave-assisted extraction (MAE). Various extraction agents, temperatures and durations of extraction were examined in order to achieve the highest efficiency of the process. The method was subjected to a validation procedure. Limits of detection (LOD = 1.76 – 14.7 ng/mL) and quantification (LOQ = 5.25 – 49.0 ng/mL), inter- (CV = 1.31 – 9.43%) and intra- (CV = 3.26 – 18.52%) day precision of the determinations, recovery (RE = 85.0–105.4%) and matrix effect on ionization of analytes (ME = 98.6–105.5%) were determined. Furthermore, the developed DBS/MAE/CM-MS method was selective and analytes present in the blood applied on DBS cards were found to be stable after 7 and after 14 days. Moreover, the developed method was successfully applied to the analysis of both post-mortem samples and blood samples taken from patients treated with the analyzed drugs.

Selective serotonin reuptake inhibitors (SSRIs) prevent meta-iodobenzylguanidine (MIBG) uptake in platelets without affecting neuroblastoma tumor uptake

BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia. While MIBG accumulates in neuroblastoma cells via selective uptake by the norepinephrine transporter (NET), the serotonin transporter (SERT) is responsible for cellular uptake of MIBG in platelets. In this study, we have investigated whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent radiotoxic MIBG uptake in platelets without affecting neuroblastoma tumor uptake.MethodsTo determine the transport kinetics of SERT for [125I]MIBG, HEK293 cells were transfected with SERT and uptake assays were conducted. Next, a panel of seven SSRIs was tested in vitro for their inhibitory potency on the uptake of [125I]MIBG in isolated human platelets and in cultured neuroblastoma cells. We investigated in vivo the efficacy of the four best performing SSRIs on the accumulation of [125I]MIBG in nude mice bearing subcutaneous neuroblastoma xenografts. In ex vivo experiments, the diluted plasma of mice treated with SSRIs was added to isolated human platelets to assess the effect on [125I]MIBG uptake.ResultsSERT performed as a low-affinity transporter of [125I]MIBG in comparison with NET (Km = 9.7 μM and 0.49 μM, respectively). Paroxetine was the most potent uptake inhibitor of both serotonin (IC50 = 0.6 nM) and MIBG (IC50 = 0.2 nM) in platelets. Citalopram was the most selective SERT inhibitor of [125I]MIBG uptake, with high SERT affinity in platelets (IC50 = 7.8 nM) and low NET affinity in neuroblastoma cells (IC50 = 11.940 nM). The in vivo tested SSRIs (citalopram, fluvoxamine, sertraline, and paroxetine) had no effect on [125I]MIBG uptake levels in neuroblastoma xenografts. In contrast, treatment with desipramine, a NET selective inhibitor, resulted in profoundly decreased xenograft [125I]MIBG levels (p < 0.0001). In ex vivo [125I]MIBG uptake experiments, 100- and 34-fold diluted murine plasma of mice treated with citalopram added to isolated human platelets led to a decrease in MIBG uptake of 54–76%, respectively.ConclusionOur study demonstrates for the first time that SSRIs selectively inhibit MIBG uptake in platelets without affecting MIBG accumulation in an in vivo neuroblastoma model. The concomitant application of citalopram during [131I]MIBG therapy seems a promising strategy to prevent thrombocytopenia in neuroblastoma patients.

Serotonin differentially modulates the temporal dynamics of the limbic response to facial emotions in male adults with and without autism spectrum disorder (ASD): a randomised placebo-controlled single-dose crossover trial

Emotion processing—including signals from facial expressions—is often altered in individuals with autism spectrum disorder (ASD). The biological basis of this is poorly understood but may include neurochemically mediated differences in the responsivity of key ‘limbic’ regions (including amygdala, ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAc)). Emerging evidence also suggests that ASD may be a disorder of brain temporal dynamics. Moreover, serotonin (5-HT) has been shown to be a key regulator of both facial-emotion processing and brain dynamics, and 5-HT abnormalities have been consistently implicated in ASD. To date, however, no one has examined how 5-HT influences the dynamics of facial-emotion processing in ASD. Therefore, we compared the influence of 5-HT on the responsivity of brain dynamics during facial-emotion processing in individuals with and without ASD. Participants completed a facial-emotion processing fMRI task at least 8 days apart using a randomised double-blind crossover design. At each visit they received either a single 20-mg oral dose of the selective serotonin reuptake inhibitor (SSRI) citalopram or placebo. We found that citalopram (which increases levels of 5-HT) caused sustained activation in key limbic regions during processing of negative facial emotions in adults with ASD—but not in neurotypical adults. The neurotypical adults’ limbic response reverted more rapidly to baseline following a 5-HT-challenge. Our results suggest that serotonergic homoeostatic control of the temporal dynamics in limbic regions is altered in adults with ASD, and provide a fresh perspective on the biology of ASD.

Synergistic antidepressant-like effect of capsaicin and citalopram reduces the side effects of citalopram on anxiety and working memory in rats

We have previously shown that in rats, capsaicin (Cap) has antidepressant-like properties when assessed using the forced swimming test (FST) and that a sub-threshold dose of amitriptyline potentiates the effects of Cap. However, synergistic antidepressant-like effects of the joint administration of Cap and the selective serotonin reuptake inhibitor citalopram (Cit) have not been reported. To assess whether combined administration of Cap and Cit has synergistic effects in the FST and to determine whether this combination prevents the side effects of Cit. Cap, Cit, and the co-administration of both substances were evaluated in a modified version of the FST (30-cm water depth) conducted in rats, as well as in the open field test (OFT), elevated plus maze (EPM), and Morris water maze (MWM). In line with previous studies, independent administration of Cap and Cit displayed antidepressant-like properties in the FST, while the combined injection had synergistic effects. In the OFT, neither treatment caused significant increments in locomotion. In the EPM, the time spent in the closed arms was lower in groups administered either only Cap or a combination of Cap and Cit than in groups treated with Cit alone. In the MWM, both Cap and the joint treatment (Cap and Cit) improved the working memory of rats in comparison with animals treated only with Cit. Combined administration of Cap and Cit produces a synergistic antidepressant-like effect in the FST and reduces the detrimental effects of Cit on anxiety and working memory.

Determination of citalopram in fish brain tissue: benefits of coupling laser diode thermal desorption with low- and high-resolution mass spectrometry.

Recent state-of-the-art methods developed for the analysis of polar xenobiotics from different types of biological matrices usually employ liquid chromatography with mass spectrometry. However, there are limitations when a small amount of sample mass is available. For example, individual benthic invertebrates or fish tissue samples often weigh less than 100mg (e.g., brain, liver) but are necessary to understand environmental fate and bioaccumulation dynamics. We developed ultra-fast methods based on a direct sample introduction technique. This included coupling laser diode thermal desorption with atmospheric pressure chemical ionization mass spectrometry (LDTD-APCI-MS). We then quantitated a common selective serotonin reuptake inhibitor (citalopram) in brain tissues of individual juvenile fish after in vivo exposure to environmentally relevant concentration. Two mass spectrometric methods based on low (LDTD-APCI-triple quadrupole (QqQ)-MS/MS) and high (LDTD-APCI-high-resolution product scan (HRPS)) resolutions were developed and evaluated. Individual instrument conditions were optimized to achieve an accurate and robust analytical method with minimum sample preparation requirements. We achieved very good recovery (97-108%) across the range of 1-100ngg-1 for LDTD-APCI-HRPS. LDTD-APCI-QqQ-MS/MS showed poorer performance due to interferences from the matrix at the lowest concentration level. LDTD-APCI ionization was successfully validated for analysis of non-filtered sample extracts. Evaluation of final methods was performed for a set of real fish brain samples, including comparison of LDTD-APCI-HRPS with a previously validated LC-heated electrospray ionization-HRPS method. This new LDTD-APCI-HRPS method avoids the chromatographic step and provides important benefits such as analysis of limited sample masses, lower total sample volume (typically μL), and reduction in analysis time per sample run to a few seconds. Graphical abstract.

Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain.

Detailed spatial information of low-molecular weight compound distribution, especially in the brain, is crucial to understanding their mechanism of actions. Imaging techniques that can directly visualize drugs in the brain at a high resolution will complement existing tools for drug distribution analysis. Here, we performed surface-enhanced Raman scattering (SERS) imaging using a bioorthogonal alkyne tag to visualize drugs directly in situ at a high resolution. Focusing on the selective serotonin reuptake inhibitor S-citalopram (S-Cit), which possesses a nitrile group, we substituted an alkynyl group into its structure and synthesized alkynylated S-Cit (Alk-S-Cit). The brain transitivity and the serotonin reuptake inhibition of Alk-S-Cit were not significantly different as compared with S-Cit. Alk-S-Cit was visualized in the coronal mouse brain section using SERS imaging with silver nanoparticles. Furthermore, SERS imaging combined with fluorescence microscopy allowed Alk-S-Cit to be visualized in the adjacent neuronal membranes, as well as in the brain vessel and parenchyma. Therefore, our multimodal imaging technique is an effective method for detecting low-molecular weight compounds in their original tissue environment and can potentially offer additional information regarding the precise spatial distribution of such drugs.

Multinational Investigation of Fracture Risk with Antidepressant Use by Class, Drug, and Indication.

OBJECTIVESAntidepressants increase the risk of falls and fracture in older adults. However, risk estimates vary considerably even in comparable populations, limiting the usefulness of current evidence for clinical decision making. Our aim was to apply a common protocol to cohorts of older antidepressant users in multiple jurisdictions to estimate fracture risk associated with different antidepressant classes, drugs, doses, and potential treatment indications.DESIGNRetrospective (2009–2014) cohort study.SETTINGFive jurisdictions in the United States, Canada, United Kingdom, and Taiwan.PARTICIPANTSOlder antidepressant users—subjects were followed from first antidepressant prescription or dispensation to first fracture or until the end of follow‐up.MEASUREMENTSThe risk of fractures with antidepressants was estimated by multivariable Cox proportional hazards models using time‐varying measures of antidepressant dose and use vs nonuse, adjusting for patient characteristics.RESULTSBetween 42.9% and 55.6% of study cohorts were 75 years and older, and 29.3% to 45.4% were men. Selective serotonin reuptake inhibitors (SSRIs) (48.4%‐60.0%) were the predominant class used in North America compared with tricyclic antidepressants (TCAs) in the United Kingdom and Taiwan (49.6%‐53.6%). Fracture rates varied from 37.67 to 107.18 per 1,000. The SSRIs citalopram (hazard ratio [HR] = 1.23; 95% confidence interval [CI] = 1.11‐1.36 to HR = 1.43; 95% CI = 1.11‐1.84) and sertraline (HR = 1.36; 95% CI = 1.10‐1.68), the SNRI duloxetine (HR = 1.41; 95% CI = 1.06‐1.88), TCAs doxepin (HR = 1.36; 95% CI = 1.00‐1.86) and imipramine (HR = 1.16; 95% CI = 1.05‐1.28), and atypicals (HR = 1.34; 95% CI = 1.14‐1.58) increased fracture risk in some but not all jurisdictions. In the United States and the United Kingdom, fracture risk with all classes was higher when prescribed for depression than chronic pain, a trend that is likely explained by drug choice.CONCLUSIONThe fracture risk for patients may be reduced by selecting paroxetine, an SSRI with lower risk than citalopram, the SNRI venlafaxine over duloxetine, and the TCA amitriptyline over imipramine or doxepin. There is uncertainty about the risk associated with the atypical antidepressants. J Am Geriatr Soc 68:1494‐1503, 2020.