Comparing the effect of fluoxetine, escitalopram, and sertraline, on the level of BDNF and depression in preclinical and clinical studies: a systematic review.

Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).

Take It Easy! Serotonin Syndrome Precipitated by the Rapid Titration of Sertraline and Trazodone in the Setting of Risperidone Use.

Serotonin syndrome is a potentially life-threatening condition caused by a toxic excess of serotonin leading to overstimulation of the nervous system. Because it is a diagnosis of exclusion, it can be underrecognized, making the true incidence unknown. The classic triad of serotonin syndrome includes neuromuscular excitation, autonomic instability and altered mental status. If left unrecognized and untreated, patients are at a high risk of mortality. The most common class of medication that carries an increased risk of serotonin syndrome, when used in combination, is selective serotonin reuptake inhibitors (SSRIs); however, medications that increase serotonin production, increase serotonin release, inhibit serotonin metabolism and stimulate serotonin receptors can increase the possibility of serotonin syndrome. We report a case that details the presentation and treatment of a 25-year-old man who developed serotonin syndrome in the setting of rapid titration of risperidone, trazodone, and sertraline. The patient presented to the ED with acute agitation, diaphoresis, and altered mental status. He also had lower extremity myoclonus and was tremulous with an oral temperature of 100°F (37.8°C) and heart rate of 103 beats per minute. Serotonin syndrome was confirmed and the patient was treated successfully with benzodiazepines before being discharged from the hospital after 4 days.

Paternal use of selective serotonin reuptake inhibitors and adverse health outcomes: A nationwide cohort study on 13,547 exposed children.

BACKGROUND: The use of selective serotonin reuptake inhibitors (SSRIs) has increased over time. Several studies indicate that paternal use of medication may adversely affect the developing fetus. Only a few studies have investigated the association between preconceptional paternal exposure to SSRIs and the risks of adverse health outcomes in children. OBJECTIVES: This study aimed to assess adverse birth outcomes and adverse early life events in children fathered by men using SSRIs prior to conception. MATERIALS AND METHODS: All live-born singleton children born in Denmark from 1997 until 2019 and their parents were included. The exposed cohort comprised all children fathered by men using SSRIs 3 months prior to conception and the unexposed cohort comprised all other children. We estimated the odds ratios for adverse birth outcomes: small for gestational age (SGA), preterm birth, low Apgar score, and major congenital malformations. Furthermore, we estimated the hazard ratios for adverse early life events of infections and hospitalizations within 1 year from birth. We also examined adverse birth outcomes and the adverse early life events according to SSRI subgroups. RESULTS: There was a statistically significantly increased odds ratio 1.15 (confidence interval, CI: 1.06-1.23) for preterm birth. No significant results were found for SGA, low Apgar score, and major congenital malformations. The adjusted hazard ratios for hospitalizations and infections were 1.06 (CI: 1.02-1.11) and 1.02 (CI: 0.97-1.07), respectively. There was a statistically significantly increased odds ratio for preterm birth with respect to the SSRI subgroups citalopram and escitalopram, and for hospitalizations with respect to citalopram. DISCUSSION AND CONCLUSION: Although the risks of certain adverse birth and adverse early life outcomes were statistically significantly increased, the ratios were small and may have limited clinical importance. Paternal use of SSRI was in general safe in the preconceptual period.

Reduced Bioavailability of Antidepressants for the Management of Generalized Anxiety Disorder Following Bariatric Surgery: A Case Study.

Bariatric surgery is a commonly performed procedure for patients who have failed to achieve weight loss through medical and lifestyle interventions. However, the altered gastrointestinal anatomy resulting from the surgery can significantly impact the bioavailability of antidepressants in patients with generalized anxiety disorder, potentially leading to uncontrolled anxiety symptoms. This case report describes a patient with generalized anxiety disorder who underwent Roux-en-Y gastric bypass surgery and subsequently experienced increased anxiety symptoms due to poor antidepressant bioavailability. The patient's medication was adjusted to a sublingual formulation, resulting in improved anxiety control and reduced side effects. Healthcare providers should be aware of the potential impact of bariatric surgery on medication absorption and closely monitor patients with generalized anxiety disorder for potential psychiatric medication-related complications postoperatively. The use of alternative routes of administration, such as sublingual medication, may be beneficial in improving drug bioavailability and managing anxiety symptoms. Creating awareness in primary care offices about poor drug absorption and using alternatives such as the sublingual route of administration to achieve optimal systemic delivery requires a multifaceted approach involving education and training for healthcare providers as well as patient education to ensure they are informed and engaged in their own care. By implementing these strategies, primary care providers can improve patient outcomes and prevent unnecessary referrals to specialists.

Tardive Dysphoria With Selective-Serotonin Reuptake Inhibitors Treated Successfully With Atypical Antidepressants: A Case Series From Tertiary Hospital Setting.

Tardive dysphoria (TDp) is a phenomenon characterized by the delayed onset or worsening of depressive symptoms following the discontinuation or alteration of antidepressant medications. TDp is a recently defined, under-recognized, and understudied condition. We present a series of five TDp cases exploring the diverse presentations, management strategies, and associated medical conditions. In all the cases, TDp manifested after prolonged use of selective serotonin reuptake inhibitors (SSRIs). All cases were successfully managed with atypical antidepressants. These cases offer insight into TDp, providing clinicians and researchers with examples of atypical trajectories in depressive symptomatology.

The Effect of Anti-Depressants on Dental Implant Failure: A Systematic Review and Meta-Analysis.

PURPOSE: The aim of this systematic review and meta-analysis is to analyze the risk of dental implant failure for patients who had a history of anti-depressant use. MATERIALS AND METHODS: An electronic search was performed up to June 2023 in three databases, including PubMed/MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials with data on comparison of implant failure rate for patients with and without the use of antidepressants were included. Meta-analyses for the risk ratio of implant failure rate at the patient level and implant level were performed. RESULTS: Eleven clinical studies were selected for inclusion in this review. The meta-analyses showed a risk ratio of 2.44 (95% confidence interval= 1.75 to 3.39, p< 0.0001) and 2.44 (95% CI= 1.73 to 3.46, p< 0.0001) for the implant failure at the patient level and implant level, respectively. The comparisons presented a low heterogeneity for the patient-level analysis and a moderate heterogeneity for the implant-level analysis among the pooled studies. Subgroup analyses also revealed that patients who received only selective serotonin reuptake inhibitors (SSRIs) or SSRIs with other type of anti-depressants had a higher risk of implant failure than those who were not on any anti-depressants. CONCLUSIONS: The current review demonstrates the use of anti-depressants, such as SSRIs, may increase the risk of dental implant failure at both patient level and implant level. Although limited evidence suggests that a certain type of SSRI (sertraline) may have more influence on implant failure than other SSRIs, future studies are needed to warrant this finding.

The Association Between Oral Bone Mineral Density-Reducing Medications and the Risk of 2-Year Implant-Related Complications Following Total Knee Arthroplasty.

BACKGROUND: Certain medications interfere with the bone remodeling process and may potentially increase the risk of complications after total knee arthroplasty (TKA). As patients undergoing TKA may be taking these bone mineral density (BMD)-reducing medications, it is unclear as to whether and which medications impact TKA outcomes. Therefore, the purpose of this study was to observe the impact of various BMD-reducing medications on 2-year implant-related complications following TKA. METHODS: A retrospective analysis of patients undergoing primary TKA was conducted using a national administrative claims database. Patients were identified if they were taking any known BMD-reducing medication and were compared to control patients. To control for confounders associated with taking multiple agents, multivariable logistic regression analyses were conducted for each 2-year outcome (all-cause revision, loosening-indicated revision, and periprosthetic fracture--indicated revision), with the output recorded as odds ratios (ORs). RESULTS: In our study, 502,927 of 1,276,209 TKA patients (39.4%) were taking at least one BMD-reducing medication perioperatively. On multivariable analysis, medications associated with a higher likelihood of 2-year all-cause revision included first- and second-generation antipsychotics (SGAs) (OR: 1.42 and 1.26, respectively), selective serotonin reuptake inhibitors (SSRIs) (OR: 1.14), glucocorticoids (1.13), and proton pump inhibitors (PPIs) (OR: 1.23) (P < .05 for all). Medications associated with a higher likelihood of 2-year periprosthetic fracture included SGAs (OR: 1.51), SSRIs (OR: 1.27), aromatase inhibitors (OR: 1.29), and PPIs (OR: 1.42) (P < .05 for all). CONCLUSIONS: Of the drug classes observed, the utilization of perioperative PPIs, SSRIs, glucocorticoids, first-generation antipsychotics, and SGAs was associated with the highest odds of all-cause revision. Our findings suggest a relationship between these medications and BMD-related complications; however, further studies should seek to determine the causality of these relationships.

Serotonin syndrome: An often-neglected medical emergency.

Optimum serotonin level in the serotonergic synapses of the central nervous system (CNS) is related to mood, behavior, and sleep. Serotonin syndrome (SS) is a rare yet very dangerous adverse effect resulting from increased serotonin in CNS. The diagnosis of SS is based on the presence of clinical symptoms, which can include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremors, sweating, and diarrhea. SS is invariably caused by inadvertent use of serotonergic medicines. There is an ever-growing list of medicines that are associated with the risk of SS. Some of the common classes of drugs that can contribute to the development of SS include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, stimulants (e.g., amphetamines and cocaine), lithium, opioids, drugs used for recreational purposes like ecstasy Methylenedioxymethamphetamine (MDMA), and some herbal supplements (e.g., St. John's Wort). SS can occur when these medications are taken alone or in combination, especially when a new medication is added, or the dose of an existing medication is changed. The management of SS typically involves discontinuing the use of the substance that caused the excess serotonin levels and providing supportive care, such as intravenous fluids and electrolytes. In severe cases, benzodiazepines may be used to control agitation and muscle rigidity, while serotonin antagonists, such as cyproheptadine, may be used to reduce serotonin levels. The literature review points to a general unawareness among physicians about the condition or drugs associated with it. Consequently, this potentially fatal condition is overlooked. There is a need for regular information updates and reminders to all those who prescribe medications to the patients.

Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19.

Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking. Materials and Methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code. Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58-0.85]; P = 4 ×10-4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 - 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Sub-chronic exposure to paroxetine disrupts ecologically relevant behaviours in fish.

The functional conservation of important selective serotonin reuptake inhibitor (SSRI) targets in non-target organisms raises concerns about their potential adverse effects on the ecosystems. Although the environmental levels of SSRIs like paroxetine (PAR) have risen, the knowledge regarding the effects of long-term exposure to PAR is limited. This study investigated the impact of sub-chronic exposure (21 days) to two sub-lethal concentrations of PAR (40 and 400 µg/L) on the behaviour of adult zebrafish in different scenarios: basal activity (under dark and light conditions), stress response (evoked by sudden light transitions) and stress response recovery. A new framework was employed for the integrative study of fish's swimming performance based on their innate ability to respond to light shifts. Several swimming-associated parameters (e.g., total swimming distance, time of inactivity, swimming angles) and thigmotaxis were monitored for an integrated analysis in each scenario. Data revealed reduced swimming activity, impaired behavioural response to stress and alterations in stress recovery of PAR-exposed fish. An anxiolytic effect was particularly noticeable in fish basal swimming activity in the dark at 400 µg/L and in the behavioural response to stress (from dark to light) and stress recovery (from light to dark) for organisms exposed to 40 µg/L. The detected PAR-induced behavioural modifications suggest a disruption of brain glucocorticoid signalling that may have implications at the individual level (e.g., changing behavioural responses to predators), with potential repercussions on the population and community levels. Therefore, the applied protocol proved sensitive in detecting behavioural changes induced by PAR.

Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

The Changes of Blood and CSF Ion Levels in Depressed Patients: a Systematic Review and Meta-analysis.

Micronutrient deficiencies and excesses are closely related to developing and treating depression. Traditional and effective antidepressants include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and lithium. There is no consensus on the fluctuation of zinc (Zn2+), magnesium (Mg2+), calcium (Ca2+), copper (Cu2+), iron (Fe2+), and manganese (Mn2+) ion levels in depressed individuals before and after therapy. In order to determine whether there were changes in blood and cerebrospinal fluid (CSF) levels of these ions in depressed patients compared with healthy controls and depressed patients treated with TCAs, SSRIs, or lithium, we applied a systematic review and meta-analysis. Using the Stata 17.0 software, we performed a systematic review and meta-analysis of the changes in ion levels in human samples from healthy controls, depressive patients, and patients treated with TCAs, SSRIs, and lithium, respectively. By searching the PubMed, EMBASE, Google Scholar, Web of Science, China National Knowledge Infrastructure (CNKI), and WAN FANG databases, 75 published analyzable papers were chosen. In the blood, the levels of Zn2+ and Mg2+ in depressed patients had decreased while the Ca2+ and Cu2+ levels had increased compared to healthy controls, Fe2+ and Mn2+ levels have not significantly changed. After treatment with SSRIs, the levels of Zn2+ and Ca2+ in depressed patients increased while Cu2+ levels decreased. Mg2+ and Ca2+ levels were increased in depressed patients after Lithium treatment. The findings of the meta-analysis revealed that micronutrient levels were closely associated with the onset of depression and prompted more research into the underlying mechanisms as well as the pathophysiological and therapeutic implications.

Antidepressants - The new endocrine disruptors? The case of crustaceans.

Antidepressants are high-volume pharmaceuticals that accumulate to concentrations in the µg·L-1 range in surface waters. The release of peptide hormones via neurosecretory cells appears as a natural target for antidepressants. Here I review research that suggests that antidepressants indeed disrupt endocrine signalling in crustaceans, by acting on the synthesis and release of neurohormones, such as crustacean hyperglycaemic hormone, moult inhibiting hormone and pigment dispersing hormone in decapods, as well as methyl farnesoate in Daphnids. Hence, antidepressants can affect hormonal regulation of physiological functions: increase in energy metabolism and activity, lowered ecdysteroid levels, potentially disrupting moult and somatic growth, reducing colour change capacity and compromising camouflage, as well as induction of male sex determination. Several studies further suggest effects of antidepressants on crustacean reproduction, but the hormonal regulation of these effects remains elusive. All things considered, a body of evidence strongly suggests that antidepressants are endocrine disrupting compounds in crustaceans.

Protocol for teen inflammation glutamate emotion research (TIGER): Toward predictors of treatment response and clinical course in depressed adolescents.

Adolescent-onset depression is a prevalent and debilitating condition commonly associated with treatment refractory depression and non-response to first-line antidepressants. There are, however, no objective tests to determine who may or may not respond to antidepressants. As depressed adolescents are especially vulnerable to the lifelong consequences of ineffectively-treated depression, it is critical to identify neurobiological predictors of treatment non-response in this population. Here, we describe the scientific rationale and protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) study, a prospective 18-month investigation of 160 depressed adolescents who will be assessed before and after treatment with selective serotonin reuptake inhibitors. TIGER will be using ultra-high field imaging to test the effects of acute stress and antidepressant treatment on inflammatory and glutamatergic processes hypothesized to underlie depression maintenance. Results from this work will motivate future studies testing alternative therapeutics for depressed adolescents at risk for treatment resistant depression. ClinicalTrials.gov Identifier: NCT05329441.

Subjective experience of the environment determines serotoninergic antidepressant treatment outcome in male mice.

BACKGROUND: The effects of the selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressant treatment, have been proposed to be affected, at least in part, by the living environment. Since the quality of the environment depends not only on its objective features, but also on the subjective experience, we hypothesized that the latter plays a key role in determining SSRI treatment outcome. METHODS: We chronically administered the SSRI fluoxetine to two groups of adult CD-1 male mice that reportedly show distinct subjective experiences of the environment measured as consistent and significantly different responses to the same emotional and social stimuli. These distinct socioemotional profiles were generated by rearing mice either in standard laboratory conditions (SN) or in a communal nest (CN) where three dams breed together their offspring, sharing caregiving behavior. RESULTS: At adulthood, CN mice displayed higher levels of agonistic and anxiety-like behaviors than SN mice, indicating that they experience the environment as more socially challenging and potentially dangerous. We then administered fluoxetine, which increased offensive and anxious response in SN, while producing opposite effects in CN mice. BDNF regulation was modified by the treatment accordingly. LIMITATIONS: Subjective experience in mice was assessed as behavioral response to the environment. CONCLUSIONS: These results show that the subjective experience of the environment determines fluoxetine outcome. In a translational perspective, our findings suggest considering not only the objective quality, but also the subjective appraisal, of the patient's living environment for developing effective personalized therapeutic approaches in psychiatry.

The effect of drug holidays on sexual dysfunction in men treated with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine: an 8-week open-label randomized clinical trial.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of various mental disorders. Sexual dysfunction is one of the most common side effects of SSRIs, and often leads to poor adherence and treatment discontinuation. While several strategies have been employed to manage SSRI-induced sexual dysfunction, drug holidays has not been extensively studied for this purpose. This clinical trial aims to assess the effect of drug holidays on sexual dysfunction in married men under treatment with SSRIs other than fluoxetine (as its long half-life makes drug holidays ineffective). METHODS: This 8-week double-center, randomized, open-label, controlled trial was conducted in the outpatient clinics of Iran Psychiatric Hospital and Tehran Institute of Psychiatry, from January 2022 to March 2023. We included married men aged between18 and 50 years who had experienced sexual dysfunction during treatment with SSRIs, other than fluoxetine. The Male Sexual Health Questionnaire (MSHQ) and the 28-Question General Health Questionnaire (GHQ-28) were used for the assessment of sexual function and mental health status. The drug holidays group was instructed not to take their medications on the weekends. The control group was asked to continue their regular medication regimen without any changes. Both groups were assessed at baseline, and weeks 4 and 8. RESULTS: Sixty-three patients were included and randomly assigned to the drug holidays group (N = 32) or the control group (N = 31). Fifty patients (25 in each group) completed the trial. Drug holidays significantly improved erection, ejaculation, satisfaction, and the overall sexual health of the participants (P < 0.001). No significant change was observed in their mental health status. No major side effects were recorded. CONCLUSIONS: Drug holidays significantly improved the MSHQ scores in 'erection', 'ejaculation', 'satisfaction' and 'total' in married men with sexual dysfunction induced by SSRIs, other than fluoxetine, without causing any significant changes in their mental health status. Further research is needed to reach a certain conclusion. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials on 2021.10.25 ( www.irct.ir ; IRCT ID: IRCT20170123032145N6) before the trial.

Melancholic features and treatment outcome to selective serotonin reuptake inhibitors in major depressive disorder: A re-analysis of the STAR*D trial.

BACKGROUND: Melancholia has been positioned as a qualitatively different form of Major Depressive Disorder (MDD). Some studies have suggested that melancholic MDD patients may show lower remission when receiving treatment with Selective Serotonin Reuptake Inhibitors, but this has not yet been explored in large, representative samples of MDD. METHODS: We used data from the STAR*D, a multisite randomized controlled trial (n = 4041). We defined melancholia status through the BA Melancholia Empirical Index, constructed using items from the Inventory of Depressive Symptomatology (IDSC). The main outcome of interest was symptomatic remission defined as a Quick Inventory of Depressive Symptoms (Clinician version) (QIDS-C) below or equal to 5. Inverse probability weighting was used to control for confounding. RESULTS: 3827 patients were eligible for this study. Melancholic patients were more likely to be unemployed, never married, to self-report an African American race, and to have a higher depressive severity. The adjusted 4-month probability of remission was 26.9 % (22.0, 45.5) for melancholic and 53.8 % (53.2, 58.5), for nonmelancholic patients. Compared with nonmelancholic, the difference in 4-month probability of remission was -26.9 % (-37.0, -15.6). Results were consistent across sensitivity analyses. LIMITATIONS: Items from IDSC were used as a surrogate measure of the BA Melancholia Index, and extrapolation of the results to agents other than citalopram and to psychotic MDD patients requires caution. CONCLUSIONS: Melancholic MDD patients showed lower probabilities of remission at 4-months receiving treatment with citalopram. The results of this study show how validly subtyping episodes could contribute to the personalized treatment of depression.

Effectiveness of antidepressants in improving the prognosis of COVID-19: A systematic review and meta-analysis.

OBJECTIVE, AND MATERIAL AND METHODS: A systematic review and meta-analysis was performed to evaluate the effectiveness of antidepressants in reducing the poor evolution of COVID-19 disease (a composite variable including death, hospitalization and need for mechanical ventilation), and mortality, according the guidelines for Systematic Reviews of Interventions published by the Cochrane library. SOURCE OF DATA: MEDLINE, EMBASE and COCHRANE LIBRARY were consulted up to February 25, 2022. Unpublished studies were searched on clinicaltrials.gov platform. SELECTION OF STUDIES: Seven masked and unmasked, observational and experimental studies evaluating death, hospitalization and need for mechanical ventilation were selected. A second subgroup analysis with mortality variable was performed. DATA EXTRACTION: A full risk of bias assessment was performed addressing issues such as information and confounding bias. ROB2 and Robins-I tools for randomized and no randomized studies were employed respectively. In the quantitative analysis, the risk of publication bias, heterogeneity, estimation of pooled measure and a sensitivity analysis was performed. The pooled final measure was calculated as odds ratio with its correspondent 95% confidence interval. A random effects model was used for this purpose due to the heterogeneity between included studies. Finally, a sensitivity analysis was performed to assess the robustness of final pooled measure. RESULTS: Seven studies were finally considered to calculate the final pooled measure. The effect of intervention was OR 0.73; 95% CI 0.56-0.94. CONCLUSIONS: The use of antidepressants, and specially SSRI could be effective for reducing the risk of poor progression of COVID-19 disease.

Protective effects of SSRI, Citalopram in mutant APP and mutant Tau expressed dorsal raphe neurons in Alzheimer's disease.

Depression is among the most common neuropsychiatric comorbidities in Alzheimer's disease (AD) and other Tauopathies. Apart from its anti-depressive and anxiolytic effects, selective serotonin reuptake inhibitor (SSRI) treatment also offers intracellular modifications that may help to improve neurogenesis, reduce amyloid burden & Tau pathologies, and neuroinflammation in AD. Despite its multifaceted impact in the brain, the exact physiological and molecular mechanism by which SSRIs such as Citalopram improve neurogenesis and synaptogenesis in dementia is poorly understood. In the current study, we investigated the protective role of SSRI, Citalopram, in serotonergic, medullary raphe neurons (RN46A-B14). RN46A-B14 cells were transfected with wild-type and mutant APP and Tau cDNAs for 24 h and then treated with 20 µM Cit for 24 h. We then assessed mRNA and protein levels of pTau, total Tau, serotonin related proteins such as TPH2, SERT, and 5HTR1a, synaptic proteins and the cytoskeletal structure. We also assessed cell survival, mitochondrial respiration and mitochondrial morphology. The mutant APP and Tau transfected cells showed increased levels of serotonin related proteins and mRNA, while the mRNA and protein levels of synaptic proteins were downregulated. Citalopram treatment significantly reduced pathologically pTau level along with the serotonin related protein levels. On the other hand, there was a significant increase in the mRNA and protein levels of synaptic genes and cytoskeletal structure in the treated groups. Further, Citalopram also improved cell survival, mitochondrial respiration and mitochondrial morphology in the treated cells that express mAPP and mTau. Taken together these findings suggest Citalopram could not only be a promising therapeutic drug for treating patients with depression, but also for AD patients.

Association between selective serotonin reuptake inhibitor use and developing irritable bowel syndrome through retrospective analysis.

BACKGROUND AND AIM: Serotonin affects the balance and integrity of the gut microbiome; however, studies have confirmed the influence of selective serotonin reuptake inhibitors (SSRIs) on irritable bowel syndrome (IBS). We evaluated the association between SSRI use and subsequent IBS occurrence in a real-world setting. METHODS: A multivariate Cox proportional hazard model was adopted, and the National Health Insurance Service cohort claims database between 2010 and 2019 was used. Non-SSRI users were selected using the propensity score matching method. Subgroup analyses were performed using the point of use, cumulative dose, and duration of SSRI use. Additional analysis was performed using a control group without psychiatric medications. RESULTS: We included 2901 SSRI users and 2727 non-SSRI users. After adjusting covariates, the risk of developing IBS in SSRI users was 1.54 times that in non-SSRI users (95% confidence interval [CI]: 1.01-2.33). The hazard ratio (HR) of the recent, heavy, and short-term user groups were 3.19 (95% CI: 2.03-4.99), 2.22 (95% CI: 1.50-3.29), and 4.83 (95% CI: 3.02-7.73), respectively, compared with that of non-users. In patients without a history of psychiatric medications, the risk of IBS incidence after SSRI use increased significantly (HR: 1.61, 95% CI: 1.06-2.42), whereas HR was insignificant in patients with a history of psychiatric medications (HR: 1.25, 95% CI: 0.98-1.60). CONCLUSIONS: The risk of subsequent IBS occurrence following SSRI use was high in patients who initially took a heavy SSRI dose and those who did not have a history of psychiatric drug use.