Common Selective Serotonin Reuptake Inhibitors Research Articles

Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability.

As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.

Exposure to a common antidepressant alters crayfish behavior and has potential subsequent ecosystem impacts

AbstractPharmaceuticals are ubiquitous in aquatic environments, yet little is known regarding their impacts on ecological processes. Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed human antidepressants and have been shown to alter crayfish behavior. These behavioral alterations are particularly relevant as crayfish play a central role in freshwater ecosystems and often reach high biomass in anthropogenically influenced environments commonly exposed to pharmaceutical contamination. Using a 14‐d artificial stream experiment, we exposed spinycheek crayfish (Faxonius limosus) to citalopram, a common SSRI, at an environmentally realistic concentration (0.5 µg/L). We used a Y‐shaped flume to quantify the effects of SSRI exposure on crayfish behavior and food/conspecific preference. We also tested the interacting effects of citalopram and crayfish on habitat‐specific and whole‐stream ecosystem functions and biomass. Crayfish exposed to SSRIs exhibited increased boldness (time to emerge from shelters; P < 0.05) and spent more time orienting to food resources than nonexposed crayfish. Crayfish increased water column chlorophyll a (P < 0.01) and benthic organic matter (P = 0.03). Furthermore, crayfish potentially increased water column respiration (P = 0.09) and potentially decreased nitrate uptake (P = 0.05). SSRI exposure exhibited a potential effect of decreasing benthic chlorophyll a (P = 0.07), but there were no significant CRAY+SSRI interactions. Neither crayfish nor SSRI treatments affected whole‐stream metabolism. These results suggest that citalopram has the potential to affect algal biomass but did not affect ecosystem functioning. However, alterations to crayfish behavior driven by SSRI exposure could lead to subsequent ecosystem‐level effects as crayfish did affect various response metrics. We were unable to detect the effects of altered crayfish behavior at the ecosystem scale during our study, likely due to the short time frame (2 weeks) of our experiment. Further work is needed to quantify longer‐term ecosystem consequences of sublethal effects of pharmaceuticals, but these results show that ecological responses to pharmaceuticals should consider the entire ecosystem.

Effects of adolescent administration of fluoxetine on novel object recognition memory, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor level

AimsFluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. Main methodsThe sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Key findingsThe present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SignificanceIn conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.

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.

Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes

BackgroundAstrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive for the role of paroxetine in astrocytic responses.MethodsIsolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed.ResultsParoxetine had no impact on LPS-stimulated iNOS, TNF-α, and IL-1β expression, but inhibited M/Lps-induced TNF-α and IL-1β expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on the activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in the viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α, and/or BDNF in astrocytes were in minor amount compared to those by microglia.ConclusionsParoxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of the NF-κB pathway but has no impact on LPS-stimulated astrocyte activation. While the effects of paroxetine on secondary astrocytic responses are not robust compared to its effect on the innate immune responses of microglia, the results together may implicate a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson’s disease.

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder

Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala. To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder. This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy. The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness. Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus. Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

Peripheral serotonin receptor 2B and transient receptor potential channel 4 mediate pruritus to serotonergic antidepressants in mice

Peripheral serotonin receptor 2B and transient receptor potential channel 4 mediate pruritus to serotonergic antidepressants in mice

What Pharmacogenetic Testing Can, Can’t Tell You About Your Patient

What Pharmacogenetic Testing Can, Can’t Tell You About Your Patient

Are SSRIs during pregnancy safe? More studies seek answers

Are SSRIs during pregnancy safe? More studies seek answers

Common Selective Serotonin Reuptake Inhibitor Side Effects in Older Adults Associated with Genetic Polymorphisms in the Serotonin Transporter and Receptors: Data from a Randomized Controlled Trial

Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care.

In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation

BackgroundAlthough several studies show that there is an increased risk of bleeding events during antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs), few studies show direct effects in vitro of SSRIs on hemostasis. MethodsThis study was undertaken to investigate the effects on platelet adhesion and plasma coagulation (APTT and PT) of two common SSRIs, citalopram and sertraline, the selective noradrenaline reuptake inhibitor reboxetine, and the serotonin and noradrenaline reuptake inhibitor venlafaxine. ResultsNone of the compounds affected plasma coagulation significantly but all compounds except for venlafaxine inhibited platelet adhesion by approximately 50% or more at the highest concentration (100μg/l, p<0.01). The potency of respective compound to inhibit platelet adhesion to both collagen and fibrinogen surfaces was in the following order; citalopram > sertraline > reboxetine. In contrast, venlafaxine caused a weak but statistically significant increased platelet adhesion to fibrinogen. ConclusionThis study showed that sertraline, citalopram and reboxetine direct and acutely decrease platelet adhesion to both collagen and fibrinogen in vitro. These results also indicate that increased risk for bleeding complications in antidepressant users may not only be explained by depletion of serotonin in platelets.

Psychiatric Treatment Received by Primary Care Patients With Panic Disorder With and Without Agoraphobia

Psychiatric Treatment Received by Primary Care Patients With Panic Disorder With and Without Agoraphobia

Mixture and single‐substance acute toxicity of selective serotonin reuptake inhibitors in Ceriodaphnia dubia

Selective serotonin reuptake inhibitors (SSRIs) are neurologically active drugs that can contaminate surface waters and have the potential to negatively affect aquatic organisms. In this investigation, the 48-h acute toxicity of mixtures (binary and quaternary) of four common SSRIs (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], and citalopram [Celexa]) were determined in the daphnid Ceriodaphnia dubia. Logistic regression was used to model mortality data and to investigate the applicability of concentration addition and independent action models to explain observed mortality. The concentrations estimated to induce 50% mortality in 48 h for the individual SSRIs sertraline, fluoxetine, paroxetine, and citalopram were 0.48 to 0.66, 1.23 to 1.84, 2.23 to 3.57, and 10.47 to 14.53 microM, respectively. Concentration addition was a better predictor of mixture effects than independent action and suggested that the tested SSRIs have a similar mechanism of action. Results indicate that environmental hazard assessments should be conservative and consider that acutely toxic effects in aquatic organisms can be additive for each SSRI in a mixture.

Antidepressants for treating depression in dementia.

The use of antidepressants for patients with dementia accompanied by depressive symptoms is widespread, but their clinical efficacy is uncertain. Many of the individual trials of antidepressants have been too small to provide precise estimates of the moderate benefits that might realistically be expected. Combining the information from all appropriate trials may provide a better estimate of the likely effects of treatment.Objectives To determine whether antidepressants are clinically effective and acceptable for the treatment of patients with depression and also dementia.Search methods The CDCIG Specialized Register was last searched on 27 April 2005. This register contains records from major health care databases and many ongoing trials databases and is updated regularly.Medical information departments of pharmaceutical companies were asked to search their databases for any relevant clinical trials. Where necessary authors of trials were approached with requests for additional information.Selection criteria All relevant unconfounded, double-blind, randomized trials comparing any antidepressant drug with placebo, for patients diagnosed as having dementia and depression, according to established criteria.Data collection and analysis Two reviewers extracted data independently and settled any differences by agreement.Main results There were seven included studies with a total of 1140 subjects of which 769 met inclusion criteria. Four included studies reported sufficiently detailed results to enter into meta-analyses, with a total of 137 subjects. Two of these studies investigated the properties of drugs not commonly used in this population with only two studies (Petracca 2001 and Lyketsos 2003) using the more common selective serotonin reuptake inhibitors (SSRIs). Lyketsos 2003 produced two significant differences in favour of treatment in the Cornell Scale for Depression in Dementia (CSDD) at 12 weeks and in the psychiatrists' global rating. However, the CSDD was not used in any of the other studies and no statistical differences were found with the other measures used in the meta-analysis. The meta-analysis of the number of patients suffering at least one adverse event, one event of the nervous system, one event of the gastrointestinal system and one event of dry mouth at 6 to 12 weeks showed a significant difference in favour of placebo. There were no other significant results.Authors' conclusions Available evidence offers weak support to the contention that antidepressants are effective for patients with depression and dementia.However, only four studies are included in the meta-analysis relating to efficacy, and sample sizes are small.Moreover, only two included studies investigated the properties of the more commonly used SSRIs and no studies investigated the properties of newer classes of antidepressants (e.g. selective noradrenergic reuptake inhibitors). This review draws attention to the paucity of research and evidence in this area.

MHA4 SSRI Antidepressant Use Patterns and their Relation to Clinical Global Impressions Scores: A Naturalistic Study

Previous studies of antidepressants in clinical practice have established a link between initial antidepressant selection and patterns of antidepressant use and health care expenditures. However, there has been far less research to date demonstrating a link between the patterns of antidepressant use and patients' clinical outcomes using data from actual clinical practice. OBJECTIVE: The purpose of this study using data from a clinical practice setting was to test whether the pattern of antidepressant use was correlated with patients' treatment response as measured by the score on the Clinical Global Impressions-Improvement scale. DATA AND METHODS: A dataset of patients who initiated therapy on one the most common selective serotonin reuptake inhibitors (SSRLs) fluoxetine, fluvoxamine, paroxetine, or sertaline in a general practitioner setting in Spain was used. A Cox proportional hazard analysis was used to predict the liklihood of treatment response based upon the pattern of initial antidepressant use, while controlling for the influence of other baseline characteristics. RESULTS: After controlling for other observed baseline characteristics including initial disease severity, patients who remained on their initial antidepressant therapy for at least two months with no switching, augmentation, or upward dose titration were 63.2% more likely (p < 0.05) than patients who had an adjustment to therapy to exprience a treatment response. CONCLUSION: The pattern of antidepressant use is an important determinant of treatment response among patients initiating therapy on the newer antidepressants in clinical practice.