Selective Serotonin Reuptake Inhibitor Citalopram Research Articles

Serotonin transporter occupancy by the SSRI citalopram predicts default-mode network connectivity

The default mode network (DMN) is an important connectivity hub, and alterations may play a role in the pathophysiology of several neuropsychiatric disorders. Despite the growing body of research on DMN (dys)function, the underlying neurochemical substrate remains to be elucidated. The serotonergic neurotransmitter system has been suggested to play a substantial role in modulating the DMN. Therefore, we investigated the association between serotonin transporter (SERT) occupancy by the selective serotonin reuptake inhibitor citalopram and DMN functional connectivity. Forty-five healthy female volunteers (mean age = 21.6y) participated in a double-dose study. The subjects were randomized to pre-treatment with placebo, a low (4 mg; ‘low group’) or clinically standard (16 mg; ‘high group’) oral citalopram dose (corresponding to 0%, ∼40% and ∼80% SERT occupancy, respectively). They underwent [123I]FP-CIT single-photon emission computed tomography (SPECT) imaging to assess SERT occupancy. In addition, resting-state functional magnetic resonance imaging was used to measure DMN connectivity. With non-parametric permutation testing we assessed the association between SERT occupancy and DMN connectivity. We found that SERT occupancy by citalopram was negatively associated with DMN connectivity with a number of cortical regions, including the anterior cingulate cortex (ACC), paracingulate gyrus, postcentral gyrus, superior parietal gyrus and temporal pole. These findings provide further neurochemical evidence that the serotonin system dose-dependently modulates DMN function.

Biphasic effects of selective serotonin reuptake inhibitors on anxiety: rapid reversal of escitalopram's anxiogenic effects in the novelty-induced hypophagia test in mice?

In humans, chronic treatment with selective serotonin reuptake inhibitors (SSRIs) decreases anxiety, unlike acute treatment, which can increase anxiety. Although this biphasic pattern is observed clinically, preclinical demonstrations are rare. In an animal model of antidepressant-induced anxiolytic effects, the novelty-induced hypophagia (NIH) test, a single administration of the SSRI citalopram reportedly elicited anxiogenic-like effects, whereas three administrations over 24 h were sufficient to produce anxiolytic-like effects. Extending these findings, the present study examined the effects of acute and repeated escitalopram in a similar NIH test in a commonly used mouse strain (i.e. C57BL/6J), analyzing results with a method (i.e. survival analysis) that can model the skewed distribution of latencies to consume food and that can deal with censored data (i.e. when consumption does not occur during the test). Saline-treated mice showed robust NIH. Acute escitalopram enhanced NIH, but did so only at a dose (i.e. 32 mg/kg) that similarly enhanced hypophagia in a familiar environment. The effects of escitalopram on NIH did not significantly change after repeated (three times) administration over 24 h. Additional studies are necessary to delineate the conditions under which rapid reversal of SSRI-induced anxiety can be modeled in animals using the NIH test.

Ebselen has lithium-like effects on central 5-HT2A receptor function.

Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq -protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions. 5-HT2A receptor function was assessed in mice by measuring the behavioural (head-twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c-fos, Egr2) responses to 5-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5-HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen enhanced the increase in extracellular 5-HT induced by citalopram, and also increased regional brain 5-HT synthesis. Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.

Transience of antidepressant‐induced Gαs signaling potentiation revealed by high‐throughput real‐time cAMP accumulation

Gαs is found at high concentrations in cholesterol rich membrane microdomains known as lipid rafts. These domains suppress coupling between Gαs and effectors such as adenylyl cyclase (AC), leading to decreased cAMP. Antidepressant drugs with diverse mechanisms of action have reliably shown the ability to promote the translocation of Gαs out of lipid rafts in cellular and animal models, leading to increased cAMP, pCREB and BDNF. In cells from depressed subjects Gαs is found at higher concentrations in lipid rafts. Importantly, this difference is eliminated in individuals who respond positively to antidepressant drug treatment, while in non‐responders the increased raft localization of Gαs is maintained. This differential localization may allow Gαs translocation out of lipid rafts to serve as a novel biomarker to screen for effective antidepressants.Although antidepressant drugs have been shown to gradually accumulate in lipid rafts, the relevant binding site, or sites, remain unknown. Notably, the S‐stereoisomer of the selective serotonin reuptake inhibitor citalopram binds to these raft regions, even in cells lacking the serotonin transporter, while the non‐antidepressant R‐stereoisomer does not. This suggests a novel, stereospecific protein target for antidepressant drugs may exist within lipid rafts. Little is known about the reversibility of this process, or whether antidepressant drug withdrawal itself produces unique signaling effects.In this study we use a combination of techniques including live cell cAMP accumulation analysis, fluorescence recovery after photobleaching (FRAP) of GFP tagged Gαs, and detection of antidepressant drug concentration via mass spectrometry. This allows determination of both the effects of extended antidepressant treatment on Gαs localization and signaling, as well as the effect of antidepressant withdrawal. Agents that increase cAMP concentrations, such as forskolin, produce greater effects following antidepressant treatment due to Gαs translocation out of lipid rafts and into closer association with AC. Gαs mobility within the membrane is also inhibited following antidepressant treatment due to formation of this Gαs/AC complex, and this reduction in mobility is observed as an increased FRAP half‐time with GFP tagged Gαs. The localization of the antidepressant drugs themselves are also quantified via mass spectrometry following separation of raft vs. non‐raft membrane regions.Analyzing these effects both during antidepressant treatment and following removal of the drug provides insight not only into the ways these drugs regulate cellular processes, but also how the cell responds to their withdrawal. It appears that antidepressant drug removal not only reverses the effects seen with extended treatment, but can also produce a lasting suppression of these processes. This work provides the next steps towards determining a binding site for antidepressants within lipid rafts, and will lead to the development of a more realistic screen for antidepressant drug development.Support or Funding InformationFunding: NIH R01AT009169; VA BX001149This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Differential consequences of early SSRI exposure upon the developing nervous system of Xenopus laevis

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for maternal depression, one of the most prevalent perinatal psychiatric conditions. Although the effects of maternal depression have been well‐characterized, there exists controversy over the adverse effects of SSRI use upon fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we narrowed our focus to investigating the outcomes of exposure to the widely‐used SSRIs fluoxetine (Prozac) and citalopram (Celexa) upon the developing nervous system through behavioral and electrophysiological assays in Xenopus laevis. Exposure concentrations and timelines in humans were translated to the X. laevis using standard dosages and dose‐response curves. Behavioral assays and whole‐cell patch‐clamp recording were performed at full maturation (stage 49). The behavioral paradigms of acoustic startle habituation and seizure susceptibility in pentylenetetrazol have established relevance to autism‐like phenotypes in X. laevis and normal neurodevelopment. Interestingly, the two SSRIs demonstrated differential abnormalities in behavior and properties of the neuron and synaptic transmission. Administration of fluoxetine during development resulted in slower habituation and increased seizure susceptibility, while exposure to citalopram led to faster habituation and decreased seizure susceptibility. We sought to explain these opposing behavioral phenotypes by whole‐cell patch‐clamp recording from the sensory‐processing tectum. We found that tectal neurons from fluoxetine‐treated animals demonstrated increased intrinsic excitability and those from citalopram‐treated animals showed decreased excitability. Moreover, citalopram‐treated neurons had increased spontaneous excitatory post‐synaptic current episodes, indicating stronger individual synaptic transmission and stronger synaptic drive. Neither group showed altered synaptic facilitation, a neurobiological mechanism related to plasticity and learning, nor an imbalance of excitatory and inhibitory projections, a circuit‐level property associated with normal neurodevelopment. These results not only support the potential role of SSRIs upon the developing brain at both the behavioral and biological levels, but complicate the discretion to administer either antidepressant. Our findings implicate the off‐target effects of fluoxetine to explain such opposing consequences, given the higher selectivity of citalopram for the serotonin reuptake transporter. Future studies will systematically probe other monoamine transporters, including those for norepinephrine and dopamine, and serotonin receptors, both of which are affected by fluoxetine. This project was funded by the American Physiological Society.Support or Funding InformationThe American Physiological SocietyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyperforin and Miquelianin from St. Johnʼs Wort Attenuate Gene Expression in Neuronal Cells After Dexamethasone-Induced Stress

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays an important part in the development of depressive symptoms. In this study, the effects of a commercial St.John's wort extract (STW3-VI), hyperforin, miquelianin, and the selective serotonin reuptake inhibitor citalopram on the expression of genes relevant to HPA axis function were investigated in human neuronal cells. SH-SY5Y cells were treated with STW3-VI (20 µg/mL), hyperforin (1 µM), miquelianin (10 µM), or citalopram (10 µM) in the presence of the glucocorticoid receptor agonist dexamethasone (DEX,10 µM) for 6 h and 48 h, respectively. Quantitative real-time polymerase chain reaction was used to determine the expression of FKBP5 (FK506 binding protein 51), CREB (cAMP responsive element binding protein), GRIK4 (glutamate ionotropic receptor kainate type subunit 4), VEGF (vascular endothelial growth factor), NET (norepinephrine transporter), and ARRB (β-arrestins), promising biomarkers of antidepressant therapy. Using DEX to mimic stress conditions, it was shown that the gene expression pattern of FKBP5, CREB, GRIK4, VEGF, NET, and ARRB2 in SH-SY5Y cells is time- and treatment-dependent. Most pronounced effects were observed for FKBP5: after 6 h of co-incubation, only STW3-VI could reverse the DEX-induced increase in FKBP5 expression, and after 48 h, citalopram, miquelianin, and hyperforin also reversed the glucocorticoid-induced increase in FKBP5 mRNA expression. The effects observed on FKBP5, CREB, GRIK4, VEGF, NET, and ARRB2 are in good correlation with published data, suggesting that this in vitro model could be used to screen the responsiveness of antidepressants under stress conditions.

Serotonin 5-HT3 receptor antagonism potentiates the antidepressant activity of citalopram

Activation of serotonin 5-HT3 receptor (5HT3R) in the locus coeruleus (LC), the principal somatodendritic noradrenergic area, decreases LC firing activity and noradrenaline (NA) release in prefrontal cortex (PFC). Blockade of 5HT3R in coadministration with selective serotonin reuptake inhibitors (SSRIs) has been proposed as a potential strategy to accelerate the onset of action of SSRIs. Dual-probe microdialysis in rats was used to evaluate the involvement of 5HT3R in the in vivo effect exerted by the SSRI citalopram on NA release. Besides, forced swimming test (FST) was carried out in mice to evaluate the antidepressant-like effect of citalopram in combination with a 5HT3R antagonist (Y25130). Systemic administration of the 5HT3R agonist SR57227 (10 mg/kg i.p.) increased NA in LC (Emax = 200 ± 27%) and PFC (Emax = 133 ± 2%). The increase in PFC was enhanced in local presence into LC of Y25130 (50 μM) (Emax = 296 ± 41%) suggesting an inhibitory function on NA release exerted by the activation of 5HT3R located in somatodendritic areas. Citalopram administration (10 mg/kg i.p.) increased NA in LC (Emax = 185 ± 11%) and decreased it in PFC (Emax = −35 ± 7%). Intra-LC (50 μM) or systemic co-administration of Y25130 (10 mg/kg i.p.) with citalopram (10 mg/kg i.p.) switched NA release in the PFC from an inhibition to a stimulatory effect. In mice FST, systemic coadministration of citalopram (2.5 mg/kg i.p.) and Y25130 (10 mg/kg i.p.) potentiated the decrease of immobility time through the increase of both swimming and climbing behaviours. These results suggest that the addition of a 5HT3R antagonist to SSRIs could represent a feasible strategy to improve antidepressant response.

The effects of serotonin modulation on medial prefrontal connectivity strength and stability: A pharmacological fMRI study with citalopram

BackgroundStatic and dynamic functional connectivity are being increasingly used to measure the effects of disease and a range of different interventions on brain networks. While preliminary evidence suggests that static connectivity can be modulated by chronic antidepressants administration in healthy individuals and in major depression, much less is known about the acute effects of antidepressants especially on dynamic functional connectivity changes. Here we examine acute effects of antidepressants on dynamic functional connectivity within the default mode network. The default mode network is a well described network with many functions in which the role of serotonin is not clear. MethodsIn this work we measured acute pharmacological effects of an infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg) in a sample of thirteen healthy volunteers randomised to receive on two occasions the active compound or placebo in a cross over dosing. ResultsAcute citalopram administration relative to placebo increased static connectivity between the medial prefrontal cortex and right dorsolateral prefrontal cortex and posterior cingulate cortex. The SSRI also induced a reduction in variability of connectivity with the medial prefrontal cortex in the precuneus and posterior cingulate cortex. DiscussionThe measured changes are compatible with modified serotonin cortical availability.

Serotonergic and cholinergic modulation of functional brain connectivity: A comparison between young and older adults

Aging is accompanied by changes in neurotransmission. To advance our understanding of how aging modifies specific neural circuitries, we examined serotonergic and cholinergic stimulation with resting state functional magnetic resonance imaging (RS-fMRI) in young and older adults. The instant response to the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was measured in 12 young and 17 older volunteers during a randomized, double blind, placebo-controlled, crossover study. A powerful dataset consisting of 522 RS-fMRI scans was obtained by acquiring multiple scans per subject before and after drug administration. Group × treatment interaction effects on voxelwise connectivity with ten functional networks were investigated (p < .05, FWE-corrected) using a non-parametric multivariate analysis technique with cerebrospinal fluid, white matter, heart rate and baseline measurements as covariates. Both groups showed a decrease in sensorimotor network connectivity after citalopram administration. The comparable findings after citalopram intake are possibly due to relatively similar serotonergic systems in the young and older subjects. Galantamine altered connectivity between the occipital visual network and regions that are implicated in learning and memory in the young subjects. The lack of a cholinergic response in the elderly might relate to the well-known association between cognitive and cholinergic deterioration at older age.

Impact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer's Dementia in Individuals With Previous Depression.

Depression is associated with an increased risk of Alzheimer's disease. Research has shown that the selective serotonin reuptake inhibitor (SSRI) citalopram decreases amyloid-β generation and plaque load. The authors evaluated the impact of SSRI treatment on CSF biomarkers and progression from mild cognitive impairment (MCI) to Alzheimer's dementia. Data sets from 755 currently nondepressed participants from the longitudinal Alzheimer's Disease Neuroimaging Initiative were evaluated by Kaplan-Meier analysis and analyses of variance and covariance with ApoE4 status and age as covariates. In MCI patients with a history of depression, long-term SSRI treatment (>4 years) was significantly associated with a delayed progression to Alzheimer's dementia by approximately 3 years, compared with short-term SSRI treatment, treatment with other antidepressants, or no treatment and compared with MCI patients without a history of depression. No differences in CSF biomarker levels were observed between treatment groups. Long-term SSRI treatment may delay progression from MCI to Alzheimer's dementia.

Developmental exposure to the SSRI citalopram causes long-lasting behavioural effects in the three-spined stickleback (Gasterosteus aculeatus)

Selective Serotonin re-uptake inhibitors (SSRIs) are a class of psychotropic drugs used to treat depression in both adolescents and pregnant or breast-feeding mothers as well as in the general population. Recent research on rodents points to long-lasting behavioural effects of pre- and perinatal exposure to SSRIs which last into adulthood. In fish however, studies on effects of developmental exposure to SSRIs appears to be non-existent. In order to study effects of developmental SSRI exposure in fish, three-spine sticklebacks were exposed to 1.5 µg/l of the SSRI citalopram in the ambient water for 30 days, starting two days post-fertilisation. After approximately 100 days of remediation in clean water the fish were put through an extensive battery of behavioural tests. Feeding behaviour was tested as the number of bites against a piece of food and found to be increased in the exposed fish. Aggression levels were measured as the number of bites against a mirror image during 10 min and was also found to be significantly increased in the exposed fish. Novel tank behaviour and locomotor activity was tested in an aquarium that had a horizontal line drawn half-way between the bottom and the surface. Neither the latency to the first transition to the upper half, nor the number of transitions or the total time spent in the upper half was affected by treatment. Locomotor activity was significantly reduced in the exposed fish. The light/dark preference was tested in an aquarium where the bottom and walls were black on one side and white on the other. The number of transitions to the white side was significantly reduced in the exposed fish but there was no effect on the latency to the first transition or the total time spent in the white half. The results in the current study indicate that developmental SSRI exposure causes long-lasting behavioural effects in fish and contribute to the existing knowledge about SSRIs as environmental pollutants.

Combinatory effects of low concentrations of 17α-etinylestradiol and citalopram on non-reproductive behavior in adult zebrafish (Danio rerio)

Sewage effluents contain pharmaceuticals, personal care products and industrial chemicals, exposing aquatic organisms to complex mixtures. The consequences of exposure to combinations of different classes of drugs in fish are largely unknown. In this study, we exposed adult zebrafish (Danio rerio) males and females for two weeks to low, environmentally relevant concentrations of the endocrine disrupting chemical 17α-etinylestradiol (EE2) and the selective serotonin re-uptake inhibitor (SSRI) citalopram, alone and in combination, and analyzed behaviors of importance for population fitness, scototaxis (light/dark preference), the novel tank test and shoal cohesion. Control water contained 0.4ng/L EE2 and the measured exposure concentrations were 0.9ng/L EE2 (nominal 0.1) and 1ng/L EE2 (nominal 0.5). The measured concentrations of citalopram were 0.1 (nominal 0.1) and 0.4μg/L (nominal 0.5). Both EE2 exposures increased anxiety in males in the scototaxis test, with significantly longer latency periods before entering and fewer visits to the white zone of the tank. The combined exposures (0.9ng/L EE2+0.1μg/L citalopram and 1ng/L EE2+0.4μg/L citalopram) resulted in abolishment of effects of EE2, with shorter latency period and more transitions to white than for fish exposed to EE2 alone. In the novel tank test, the results surprisingly indicated lower anxiety after both EE2 and citalopram exposure. Significantly more transitions to the upper half of the tank observed in males exposed to 0.1μg/L citalopram alone compared to control males. Males exposed to EE2 (0.9ng/L) had shorter latency period to the upper half. Combination exposure resulted in a longer latency and fewer transitions to the upper half compared to both control, EE2- and citalopram-exposed males. Males exposed to the combination spent significantly less time in the upper half than males EE2 or citalopram-exposed males. Females exposed to 1ng/L EE2 had fewer transitions to the upper half than the control group and females exposed to 0.4μg/L citalopram. In the shoaling test, males exposed to 0.1μg/L citalopram+0.9ng/L EE2 showed more transitions away from peers than males exposed to 0.1μg/L citalopram alone. In conclusion, low concentrations of EE2, closely above the predicted no effect concentration (NOEC) of 0.1ng/L, created anxiety-like behavior in zebrafish males. Citalopram showed marginal effects at these low concentrations but in the combination exposure the behavioral effects of EE2 were abolished. This is an initial effort to understand the effects of cocktails of anthropogenic substances contaminating aquatic environments.

Mouse strain differences in SSRI sensitivity correlate with serotonin transporter binding and function

Selective serotonin reuptake inhibitors (SSRIs) bind 5-HT transporters, leading to the accumulation of 5-HT and amelioration of depression. Although different mouse strains show varying sensitivity to SSRIs in mouse models of depression, the underlying mechanism of these strain differences remains unclear. Here, the SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2J mice but not C57BL/6J mice, whereas fluoxetine showed the opposite results. Paroxetine similarly reduced immobility time in both strains. The affinity of citalopram for the 5-HT transporter was 700-fold higher in DBA/2J mice than in C57BL/6J mice, whereas the affinity of fluoxetine was 100-fold higher in C57BL/6J mice than in DBA/2J mice. Furthermore, high citalopram concentrations were required for [3H]5-HT uptake in C57BL/6J but not in DBA/2J mouse cortical synaptosomes, whereas fluoxetine showed the opposite results. The effects of paroxetine on 5-HT transporter binding and synaptosomal 5-HT uptake were similar in the two strains. These results suggest that immobility duration depends on 5-HT transporter binding levels, which lead to apparent strain differences in immobility time in the FST and TST. Furthermore, differences in 5-HT transporter binding may cause variations in SSRI effects on behaviors.

Further Evaluation of Mechanisms Associated with the Antidepressantlike Signature of Scopolamine in Mice.

Conventional antidepressants lack efficacy for many patients (treatmentresistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action. Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature with ketamine or scopolamine when studied under the forced-swim test. The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (AZD8055) also attenuated the antidepressant- like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant- like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action. Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.

Cross-species studies of cognition relevant to drug discovery: a translational approach.

This review advances the case that bidirectional, cross-species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross-species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenaline reuptake blocker atomoxetine. Functional neuroimaging evidence suggests a modulation of circuitry including the inferior prefrontal cortex by this drug. Parallel work in rats had shown that atomoxetine improves stop signal performance by affecting possibly homologous regions of the rodent prefrontal cortex. This parallel effect of atomoxetine in rodents and humans could potentially be exploited in other disorders in which impulsivity plays a role, such as stimulant abuse and Parkinson's disease. A contrasting relative lack of involvement of 5-HT mechanisms in the stop signal reaction time task will also be described. Research in humans and experimental animals that demonstrate effects of serotoninergic agents such as the selective serotonin (5-HT) reuptake inhibitor citalopram on probabilistic learning and reversal (upon which atomoxetine has little effect) will also be reviewed, possibly relevant to the treatment of clinical depression, Finally, other promising examples of parallel studies of behavioural effects of CNS-active drugs in animals and humans will also be described. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

Simultaneous determination of selective serotonin reuptake inhibitors and their main metabolites in human breast milk by liquid chromatography-electrospray mass spectrometry.

A bioanalytical method by high performance liquid chromatography coupled to electrospray mass spectrometry (HPLC-ESI-MS), adapted from a previously published method in plasma, was validated in breast milk for the simultaneous quantification of all antidepressants belonging to the class of selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their major metabolites (desmethylcitalopram and norfluoxetine). Milk samples (250μl) first underwent protein precipitation followed by solid-phase extraction on a reversed phase/cation exchange sorbent. Analytes were thereafter separated on a XBridge C18 column (2.1mm×100mm; 3.5μm) using a mobile phase composed of ammonium acetate buffer (pH 8.1; 50mM) and acetonitrile in gradient mode. Detection was performed by a single quadrupole mass spectrometer running in selected ion monitoring in positive ionization mode. Method validation covered a wide concentration range of 2-500ng/ml for citalopram, desmethylcitalopram and paroxetine, 5-500ng/ml for sertraline, and 2-1000ng/ml for fluoxetine, norfluoxetine and fluvoxamine. Validation performances such as trueness (90.3-111.6%), repeatability (0.8-9.3%) and intermediate precision (0.9-9.5%) were in agreement with criteria from international guidelines and matrix effects for the analyte/internal standard ratios ranged from 92% to 110% (relative standard deviation <15%). Accuracy profiles (total error of trueness and precision) were lying within the limits of ±30% accepted in bioanalysis. Finally, the method was successfully applied to patient samples collected in a clinical pharmacokinetic study of nursing mothers taking an antidepressant treatment.

Duloxetine augmentation in resistant obsessive compulsive disorder: Surveying a new medication for challenges in treatment of OCD

IntroductionUp to 50% of patients with OCD have failed to respond in SSRI trials, so looking for pharmacological alternatives in treatment of obsessive compulsive disorder (OCD) seems necessary.ObjectivesSurveying duloxetine augmentation in treatment of resistant OCD.AimsStudy the effects of serotonin-norepinephrine enhancers for treatment of OCD.MethodsThis augmentation trial was designed as an 8-week randomized controlled, double blind study. Forty-six patients suffering from OCD who had failed to respond to at least 12 weeks of treatment with a selective serotonin reuptake inhibitor (fluoxetine, citalopram or fluvoxamine) were randomly allocated to receive duloxetine or sertraline plus their current anti OCD treatment. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the primary outcome measure.ResultsForty-six patients (24 of 30 in duloxetine group and 22 of 27 in sertraline group) completed the trial. Both groups showed improvement over the 8-week study period (mean Y-BOCS total score at week 8 as compared with baseline: P &lt; 0.001 and P &lt; 0.001) without significant difference (P = 0.861). Those receiving duloxetine plus their initial medications experienced a mean decrease of 33.0% in Y-BOCS score and the patients with sertraline added to their initial medication experienced a mean decrease of 34.5% in Y-BOCS.ConclusionsOur double blind controlled clinical trial showed duloxetine to be as effective as sertraline in reducing obsessive and compulsive symptoms in resistant OCD patients. However, it needs to be noted that our study is preliminary and larger double blind placebo controlled studies are necessary to confirm the results.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Magnetic carbon nanotubes modified with 1,4-diazabicyclo[2.2.2] octane are a viable sorbent for extraction of selective serotonin reuptake inhibitors

Carbon nanotubes were modified with magnetite nanoparticles, and 1,4-diazabicyclo[2.2.2]octane (DABCO) was then covalently attached to their surface. The resulting material is shown to be a viable sorbent for the preconcentration of the selective serotonin reuptake inhibitors citalopram, sertraline, fluvoxamine and fluoxetine via ultrasound-assisted magnetic solid phase extraction. The effects of pH value, sorbent dosage, eluent volume and salt concentration were optimized by central composite design and desirability function. The drugs were quantified by HPLC with UV detection. Detection limits are as low as 0.2, 0.25, 0.3, and 0.5 ng mL−1 for citalopram, sertraline, fluvoxamine and fluoxetine, respectively. The intra-day precisions (RSDs) are 91%. The sorbent can be reused 12 times without a noticeable decrease in extraction efficiency.

Effects of acute dopaminergic and serotonergic manipulations in the ACI paradigm depend on the basal valence of cognitive judgement bias in rats

Recent findings have revealed that pharmacological enhancement of dopaminergic (DA) function by the administration of a DA precursor (dihydroxy-l-phenylalanine; L-DOPA), but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increases an optimism bias in humans. To test whether dopamine might play a similar role in non-human animals, in the present study, we evaluated the effects of acute injections of L-DOPA, the D2 receptor antagonist haloperidol, and the SSRI escitalopram on cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. Three different doses of each drug were administered in a fully randomised Latin-square design, along with saline treatment as a control, 30min before the ACI tests. Initial analysis revealed that only animals treated with L-DOPA were more ‘pessimistic’ than the saline-treated controls. Neither haloperidol nor escitalopram significantly affected the cognitive judgement bias of rats. However, further analysis revealed that the effects of the tested compounds might depend on the basal cognitive judgement bias of the tested animals. When we divided the rats into ‘optimistic’ and ‘pessimistic’ groups based on their cognitive judgement bias in the drug-free state, it turned out that acute administration of L-DOPA caused a ‘pessimistic’ shift in ‘optimistic’ animals while showing no significant effects on ‘pessimists’. Acute administration of haloperidol caused a ‘pessimistic’ shift in ‘optimistic’ animals and an ‘optimistic’ shift in ‘pessimists’. Acute administration of escitalopram caused a ‘pessimistic’ shift in ‘optimistic’ animals and had no significant effects on ‘pessimists’, except that the middle tested dose rendered the rats more ‘optimistic’.

Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α2-adrenoceptors in rat brain

Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α2-adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α2-adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [35S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α2-adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (Emax = −44 ± 4%; p < 0.001) and in PFC (Emax = −61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (Emax = −25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (Emax = −36 ± 4%). Clonidine administration (0.625–20 μg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED50 = 3.2 ± 0.4 μg/kg) and saline-treated groups (ED50 = 2.6 ± 0.5 μg/kg). No significant differences between groups were found in ED50 values. The α2-adrenoceptor agonist UK14304 stimulated specific [35S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α2-adrenoceptors acting as axon terminal autoreceptors in PFC without changes in somatodendritic α2-adrenoceptor sensitivity.