Effectiveness of Antidepressants in Combination with Psychotherapy.

BACKGROUND: Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no specific advice on which antidepressant is best for a given medical history. AIMS OF THE STUDY: For patients with major depression who are in psychotherapy, this study provides an empirically derived guideline for prescribing antidepressant medications that fit patients' medical history. METHODS: This retrospective, observational, cohort study analyzed a large insurance database of 3,678,082 patients. Data was obtained from healthcare providers in the U.S. between January 1, 2001, and December 31, 2018. These patients had 10,221,145 episodes of antidepressant treatments. This study reports the remission rates for the 14 most commonly prescribed single antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine) and a category named "Other" (other antidepressants/combination of antidepressants). The study used robust LASSO regressions to identify factors that affected remission rate and clinicians' selection of antidepressants. The selection bias in observational data was removed through stratification. We organized the data into 16,770 subgroups, of at least 100 cases, using the combination of the largest factors that affected remission and selection bias. This paper reports on 2,467 subgroups of patients who had received psychotherapy. RESULTS: We found large, and statistically significant, differences in remission rates within subgroups of patients. Remission rates for sertraline ranged from 4.5% to 77.86%, for fluoxetine from 2.86% to 77.78%, for venlafaxine from 5.07% to 76.44%, for bupropion from 0.5% to 64.63%, for desvenlafaxine from 1.59% to 75%, for duloxetine from 3.77% to 75%, for paroxetine from 6.48% to 68.79%, for escitalopram from 1.85% to 65%, and for citalopram from 4.67% to 76.23%. Clearly these medications are ideal for patients in some subgroups but not others. If patients are matched to the subgroups, clinicians can prescribe the medication that works best in the subgroup. Some medications (amitriptyline, doxepin, nortriptyline, and trazodone) always had remission rates below 11% and therefore were not suitable as single antidepressant therapy for any of the subgroups. DISCUSSIONS: This study provides an opportunity for clinicians to identify an optimal antidepressant for their patients, before they engage in repeated trials of antidepressants. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: To facilitate the matching of patients to the most effective antidepressants, this study provides access to a free, non-commercial, decision aid at http://MeAgainMeds.com. IMPLICATIONS FOR HEALTH POLICIES:  Policymakers should evaluate how study findings can be made available through fragmented electronic health records at point-of-care. Alternatively, policymakers can put in place an AI system that recommends antidepressants to patients online, at home, and encourages them to bring the recommendation to their clinicians at their next visit. IMPLICATIONS FOR FURTHER RESEARCH:  Future research could investigate (i) the effectiveness of our recommendations in changing clinical practice, (ii) increasing remission of depression symptoms, and (iii) reducing cost of care. These studies need to be prospective but pragmatic. It is unlikely random clinical trials can address the large number of factors that affect remission.

Parental exposure to antidepressants has lasting effects on offspring? A case study with zebrafish.

Fish have common neurotransmitter pathways with humans, exhibiting a significant degree of conservation and homology. Thus, exposure to fluoxetine makes fish potentially susceptible to biochemical and physiological changes, similarly to what is observed in humans. Over the years, several studies demonstrated the potential effects of fluoxetine on different fish species and at different levels of biological organization. However, the effects of parental exposure to unexposed offspring remain largely unknown. The consequences of 15-day parental exposure to relevant concentrations of fluoxetine (100 and 1000 ng/L) were assessed on offspring using zebrafish as a model organism. Parental exposure resulted in offspring early hatching, non-inflation of the swimming bladder, increased malformation frequency, decreased heart rate and blood flow, and reduced growth. Additionally, a significant behavioral impairment was also found (reduced startle response, basal locomotor activity, and altered non-associative learning during early stages and a negative geotaxis and scototaxis, reduced thigmotaxis, and anti-social behavior at later life stages). These behavior alterations are consistent with decreased anxiety, a significant increase in the expression of the monoaminergic genes slc6a4a (sert), slc6a3 (dat), slc18a2 (vmat2), mao, tph1a, and th2, and altered levels of monoaminergic neurotransmitters. Alterations in behavior, expression of monoaminergic genes, and neurotransmitter levels persisted until offspring adulthood. Given the high conservation of neuronal pathways between fish and humans, data show the possibility of potential transgenerational and multigenerational effects of pharmaceuticals' exposure. These results reinforce the need for transgenerational and multigenerational studies in fish, under realistic scenarios, to provide realistic insights into the impact of these pharmaceuticals.

Temperature-dependent toxicity of fluoxetine alters the thermal plasticity of marine diatoms.

Anthropogenic activities have led to the emergence of pharmaceutical pollution in marine ecosystems, posing a significant threat to biodiversity in conjunction with global climate change. While the ecotoxicity of human drugs on aquatic organisms is increasingly recognized, their interactions with environmental factors, such as temperature, remain understudied. This research investigates the physiological effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine, on two diatom species, Phaeodactylum tricornutum and Thalassiosira weissflogii. Results demonstrate that fluoxetine significantly reduces growth rate and biomass production, concurrently affecting pigment contents and the thermal performance curve (TPC) of the diatoms. Fluoxetine reduces the synthesis of chlorophyll a (Chl a) and carotenoid (Car), indicating inhibition of photosynthesis and photoprotection. Furthermore, fluoxetine decreases the maximum growth rate (µmax) while increasing the optimum temperature (Topt) in both species, suggesting an altered thermal plasticity. This shift is attributed to the observed decrease in the inhibition rate of fluoxetine with rising temperatures. These findings emphasize the physiological impacts and ecological implications of fluoxetine on phytoplankton and underscore the significance of considering interactions between multiple environmental drivers when accessing the ecotoxicity of potential pollutants. The present study provides insights into crucial considerations for evaluating the impacts of pharmaceutical pollution on marine primary producers.

Polystyrene microplastics alter the trophic transfer and biotoxicity of fluoxetine in an aquatic food chain.

Microplastics (MPs) and fluoxetine are ubiquitous emerging pollutants in aquatic environments that may interact with each other due to the carrier effects of MPs, posing unpredictable risks to non-target organisms. However, limited studies have focused on the carrier effects of MPs in the aquatic food chain. This study evaluated the influences of polystyrene MPs on the trophic transfer and biotoxicity of fluoxetine in a simple food chain composed of brine shrimp (Artemia nauplii) and zebrafish (Danio rerio). The finding reveals that carrier effects of MPs enhanced the accumulation of waterborne fluoxetine in brine shrimp, but suppressed that in zebrafish due to the distinct retention times. The accumulated fluoxetine in shrimp was further transferred to fish through the food chain, which was alleviated by MPs due to their cleaning effects. In addition, the specific neurotransmission biotoxicity in fish induced by fluoxetine was mitigated by MPs, whilst the oxidative damage, apoptosis, and immune responses in zebrafish were reversely enhanced by MPs due to the stimulating effect. These findings highlight the alleviating effects of MPs on the trophic transfer and specific biotoxicity of fluoxetine in the food chain, providing new insights into the carrier effects of MPs in aquatic environments in the context of increasing global MP pollution.

Fluoxetine and Sertraline Potently Neutralize the Replication of Distinct SARS-CoV-2 Variants.

The pandemic caused by SARS-CoV-2 is still a major health problem. Newly emerging variants and long-COVID-19 represent a challenge for the global health system. In particular, individuals in developing countries with insufficient health care need easily accessible, affordable and effective treatments of COVID-19. Previous studies have demonstrated the efficacy of functional inhibitors of acid sphingomyelinase against infections with various viruses, including early variants of SARS-CoV-2. This work investigated whether the acid sphingomyelinase inhibitors fluoxetine and sertraline, usually used as antidepressant molecules in clinical practice, can inhibit the replication of the former and recently emerged SARS-CoV-2 variants in vitro. Fluoxetine and sertraline potently inhibited the infection with pseudotyped virus-like particles and SARS-CoV-2 variants D614G, alpha, delta, omicron BA.1 and omicron BA.5. These results highlight fluoxetine and sertraline as priority candidates for large-scale phase 3 clinical trials at different stages of SARS-CoV-2 infections, either alone or in combination with other medications.

Early Chronic Fluoxetine Treatment of Ts65Dn Mice Rescues Synaptic Vesicular Deficits and Prevents Aberrant Proteomic Alterations.

Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS.

The oxytocin receptor is essential for the protective effect of pair housing on post-stroke depression in mice.

The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1ß, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice.

We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

Impact of chronic fluoxetine exposure on zebrafish: From fatty acid profile to behavior.

The consumption of antidepressants, such as fluoxetine, has increased over the years and, as a result, they are increasingly found in aquatic systems. Given the increasing use of zebrafish as an animal model in toxicological studies, this work proposed to evaluate the effects of chronic exposure, for 21 days, to fluoxetine at environmentally relevant concentrations (1, 10, 100, and 1000 ng/L). The behavioral tests performed did not reveal significant effects of fluoxetine. However, oxidative stress and changes in energy metabolism were detected after exposure to the highest concentrations of fluoxetine tested, namely a decrease in glutathione S-transferase (GST) activity (decrease of ca. 31%), increase in catalase (CAT) activity (increase of ca. 71%), and decrease in lactate dehydrogenase (LDH) activity (decrease of ca. 53%). Analysis of the fatty acid profile (FA) revealed a decrease in the omega-3 FA, docosahexaenoic acid (DHA), C22:6 (decrease in relative abundance between 6% and 8% for both the head and body), an increase in omega-6 FA, linoleic acid (LA), C18:2, (increased relative abundance between 8% and 11% in the head and between 5% and 9% in the body), which may suggest changes in the inflammatory state of these organisms. The integrated analysis adopted proved to be useful in detecting subindividual effects of fluoxetine and modes of action in fish.

The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder.

BACKGROUND: Inflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear. METHODS: Forty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6-8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1ß, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment. RESULTS: Serum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1ß, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1ß, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents. CONCLUSIONS: Our study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

Efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination in post-schizophrenic depression: A randomized controlled trial.

Post-schizophrenic depression (PSD) increases the morbidity, mortality, and health burden in patients with schizophrenia. However, treatment of PSD is challenging due to the lack of substantial evidence of standard clinical practice. This study was aimed at comparing the efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination (OFC) in PSD. This was a randomized controlled trial conducted in sixty patients with PSD fulfilling the eligibility criteria. Recruited patients were randomized to receive either amisulpride at low dose (i.e., 100-300 mg/day) or OFC (5/10 mg + 20 mg) for eight weeks. The Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression-Severity (CGI-S) and serum BDNF levels were assessed at baseline and after eight weeks of treatment. The change in the CDSS scores from baseline over eight weeks was significant in both the amisulpride and OFC groups. However, the changes were not significant when compared between the groups. Similarly, the changes in CGI-S scores and serum BDNF levels were significant in each group; but non-significant between the groups. A significant negative correlation was found between the changes in the CDSS scores and the serum BDNF levels in each group. No significant adverse events were noted in either group. Thus, to conclude, low-dose amisulpride can be a potential monotherapy in PSD with a favourable clinical outcome and safety profile (ClinicalTrials.gov ID: NCT04876521).

Neonatal hypoxia impairs serotonin release and cognitive functions in adult mice.

Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.

Prenatal Fluoxetine Exposure Influences Glucocorticoid Receptor-Mediated Activity in the Prefrontal Cortex of Adolescent Rats Exposed to Acute Stress.

Any deviation from the programmed processes of brain development may modify its formation and functions, thereby precipitating pathological conditions, which often become manifest in adulthood. Exposure to a challenge during crucial periods of vulnerability, such as adolescence, may reveal molecular changes preceding behavioral outcomes. Based on a previous study showing that prenatal fluoxetine (FLX) leads to the development of an anhedonic-like behavior in adult rats, we aimed to assess whether the same treatment regimen (i.e., fluoxetine during gestation; 15 mg/kg/day) influences the ability to respond to acute restraint stress (ARS) during adolescence. We subjected the rats to a battery of behavioral tests evaluating the development of various phenotypes (cognitive deficit, anhedonia, and anxiety). Furthermore, we carried out molecular analyses in the plasma and prefrontal cortex, a brain region involved in stress response, and whose functions are commonly altered in neuropsychiatric conditions. Our findings confirm that prenatal manipulation did not affect behavior in adolescent rats but impaired the capability to respond properly to ARS. Indeed, we observed changes in several molecular key players of the hypothalamic pituitary adrenal axis, particularly influencing genomic effects mediated by the glucocorticoid receptor. This study highlights that prenatal FLX exposure influences the ability of adolescent male rats to respond to an acute challenge, thereby altering the functionality of the hypothalamic-pituitary-adrenal axis, and indicates that the prenatal manipulation may prime the response to challenging events during this critical period of life.

Nanoplastics increase in vitro oestrogenic activity of neurotherapeutic drugs.

Environmental pollution with plastic nanoparticles (PNPs) has rendered hazard assessment of unintentional human exposure to neurotherapeutic drugs through contaminated water and food ever more complicated. Due to their small size, PNPs can easily enter different cell types and cross different biological barriers, while their high surface-to-volume ratio enables higher adsorption of chemicals. This is how PNPs take the role of a Trojan horse as they enhance bioaccumulation of many different pollutants. One of the health concerns related to water pollution with neurotherapeutic drugs is endocrine disruption, already evidenced for the anticonvulsant drug carbamazepine (Cbz) and antidepressant fluoxetine (Flx). Our study aimed to evaluate endocrine disrupting effects of Cbz and Flx in mixtures with polystyrene nanoparticles (PSNPs) using the in vitro luciferase assay to measure oestrogen receptor activity in T47D-KBluc cells treated with Cbz-PSNPs or Flx-PSNPs mixtures and compare it with the activities observed in cells treated with individual mixture components (Cbz, Flx, or PSNPs). Dose ranges used in the study were 0.1-10 mg/L, 1-100 µmol/L, and 0.1-10 µmol/L for PSNPs, Cbz, and Flx, respectively. Our findings show that none of the individual components activate oestrogen receptors, while the mixtures induce oestrogen receptor activity starting with 0.1 mg/L for PSNPs, 10 µmol/L for Cbz, and 0.5 µmol/L for Flx. This is the first study to evidence that PSNPs increase oestrogen receptor activity induced by neurotherapeutic drugs at their environmentally relevant concentrations and calls for urgent inclusion of complex mixtures in health hazard assessments to inform regulatory response.

Psychoactive substance consumption after the Fundão dam mine tailing disaster in Minas Gerais State, Brazil.

Disasters cause changes in morbidity, mortality, and medicine use. Brazil is one of the main producers of mineral ores at great environmental cost. Mine tailings are stored in dams and ruptures have led to major disasters. We investigated the consumption of psychoactive medicines in the municipalities affected by the Fundão dam disaster in Minas Gerais State. An ecological study was carried out on drug consumption, estimated using public purchases in Minas Gerais and dispensing data from private retail pharmacies. Consumption (in number of defined daily doses/100,000 inhabitants per day) was analyzed descriptively in eight municipalities, stratified according to consumption level during a 25-month period. Six comparisons of mean consumption values for both data sets were done for pre- and post-disaster periods. The means of medicine consumption before and after the event were plotted and linear trends were added. Public purchase data evinced high consumption levels. Only pharmaceutical retail showed significant differences between the strata in the pre-disaster versus two post-disaster periods. Smaller municipalities showed an increase in consumption 15 months after the disaster. Clonazepam led the way in pharmaceutical retail consumption, followed by fluoxetine. Medicines showed an upward trend after the disaster. The high public provision may have stifled significant consumption patterns of psychoactive drugs; however, peak consumption were observed in private retail, suggesting a modification in use patterns after the disaster. The decrease in consumption immediately after the event was probably related to lower care-seeking behavior on the part of the population, and significant peaks after the disaster may reflect economic consequences of it.

Quercetin attenuates brain apoptosis in mice with chronic unpredictable mild stress-induced depression.

BACKGROUND: Depression is a common psychiatric disorder with limited effective treatments. Research suggests that depression involves apoptosis mechanisms. Quercetin (QUE) has been reported to have anti-apoptotic activities. In this study, we aimed to investigate the effects and mechanisms of QUE in chronic unpredictable mild stress (CUMS)-induced depression. METHODS: After establishing mouse models of CUMS-induced depression, the mice were randomly assigned into four groups: control, CUMS, CUMS+QUE, and CUMS+Fluoxetine (FLX). The body weight of the mice was measured during the study. Then, depression-associated behaviors were evaluated using the sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST) and tail suspension test (TST). Apoptosis in the hippocampus and prefrontal cortex was determined using flow cytometry. Bcl-2 and Nrf2 protein expressions in the hippocampus and prefrontal cortex were also detected. Furthermore, Western blot was used to measure the protein levels of p-ERK, ERK, p-CREB, CREB, and Nrf2 in brain tissues. RESULTS: QUE or FLX administration increased the body weight of the CUMS mice. Behavioral tests indicated that CUMS mice developed a state of depression, but QUE or FLX treatment improved their depression-associated behaviors. Meanwhile, QUE or FLX treatment decreased apoptosis in the hippocampus and prefrontal cortex. Furthermore, the decreased Nrf2 protein expression, ERK and CREB phosphorylation in CUMS group were enhanced by QUE or FLX administration. CONCLUSION: QUE could attenuate brain apoptosis in mice with CUMS-induced depression, and the mechanism may be related to the ERK/Nrf2 pathway, indicating that QUE could be a potential treatment for depression.

Integrated physio-biochemical and transcriptomic analysis reveals the joint toxicity mechanisms of two typical antidepressants fluoxetine and sertraline on Microcystis aeruginosa.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are of increasing concern worldwide due to their ubiquitous occurrence and detrimental effects on aquatic organisms. However, little is known regarding their effects on the dominant bloom-forming cyanobacterium, Microcystis aeruginosa. Here, we investigated the individual and joint effects of two typical SSRIs fluoxetine (FLX) and sertraline (SER) on M. aeruginosa at physio-biochemical and molecular levels. Results showed that FLX and SER had strong growth inhibitory effects on M. aeruginosa with the 96-h median effect concentrations (EC50s) of 362 and 225 µg/L, respectively. Besides, the mixtures showed an additive effect on microalgal growth. Meanwhile, both individual SSRIs and their mixtures can inhibit photosynthetic pigment synthesis, cause oxidative damage, destroy cell membrane, and promote microcystin-leucine-arginine (MC-LR) synthesis and release. Moreover, the mixtures enhanced the damage to photosynthesis, antioxidant system, and cell membrane and facilitated MC-LR synthesis and release compared to individuals. Furthermore, transcriptomic analysis revealed that the dysregulation of the key genes related to transport, photosystem, protein synthesis, and non-ribosomal peptide structures was the fundamental molecular mechanism underlying the physio-biochemical responses of M. aeruginosa. These findings provide a better understanding of the toxicity mechanisms of SSRIs to microalgae and their risks to aquatic ecosystems.

The hippocampal salt-inducible kinase 2-CREB-regulated transcription co-activator 1 system mediates the antidepressant actions of paroxetine in mice.

The hippocampal salt-inducible kinase 2 (SIK2)-CREB-regulated transcription co-activator 1 (CRTC1) system has been demonstrated to participate in not only the pathogenesis of depression but also the antidepressant mechanisms of several antidepressant medications including fluoxetine, paroxetine, and mirtazapine. Like fluoxetine, paroxetine is also a widely used selective serotonin (5-HT) reuptake inhibitor (SSRI). Recent studies have indicated that paroxetine also modulates several pharmacological targets other than the 5-HT system. Here, we speculate that paroxetine regulates the hippocampal SIK2-CRTC1 system. Chronic stress models of depression, various behavioral tests, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription PCR, and genetic knockdown were used together in the present study. Our results show that the antidepressant actions of paroxetine in mice models of depression were accompanied by its preventing effects against chronic stress on hippocampal SIK2, CRTC1, and CRTC1-CREB binding. In contrast, genetic knockdown of hippocampal CRTC1 notably abrogated the antidepressant effects of paroxetine in mice. In summary, regulating hippocampal SIK2 and CRTC1 participates in the antidepressant mechanism of paroxetine, extending the knowledge of its pharmacological targets.