Serotonin-norepinephrine Reuptake Inhibitors Research Articles

A systematic review and meta-analysis of randomized controlled head-to-head trials of recommended drugs for neuropathic pain.

Neuropathic pain is a challenging chronic pain condition. Limited knowledge exists regarding the relative effectiveness of pharmacological treatments, and differences in trial design and impact of the placebo response preclude indirect comparisons of efficacy between drug classes. The purpose of this systematic review and meta-analysis of head-to-head trials was to compare the efficacy and tolerability of drugs recommended for neuropathic pain. We conducted a systematic review and meta-analysis of direct-comparison double-blind randomized trials. Primary outcomes were mean change in pain intensity and number of responders with a 50% reduction in pain intensity. Secondary outcomes encompassed quality of life, sleep, emotional functioning, and number of dropouts because of adverse events. We included 30 trials (4087 patients), comprising 16 crossover and 14 parallel-group design studies. All studies were conducted in adults, and the majority were investigator-initiated trials. We found moderate-quality evidence for equivalence (no clinically relevant difference) between tricyclic antidepressants (TCA) and gabapentin/pregabalin with a combined mean difference in pain score of 0.10 (95% CI -0.13 to 0.32). We could not document differences between TCA and serotonin-noradrenaline reuptake inhibitors (SNRI), between SNRI and gabapentin/pregabalin, or between opioids and TCA (low quality of evidence). We found more dropouts because of adverse events with SNRI and opioids compared with TCA (low quality of evidence). We did not identify any studies that included topical treatments. This systematic review of direct-comparison studies found evidence for equivalence between TCA and gabapentin/pregabalin and fewer dropouts with TCA than SNRI and opioids.

Trajectory and magnitude of response in adults with anxiety disorders: a Bayesian hierarchical modeling meta-analysis of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and benzodiazepines.

How the trajectory of response to medication (and placebo response) varies among selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines and across anxiety disorders is unknown. We performed a meta-analysis using weekly symptom severity data from randomized, parallel-group, placebo-controlled trials of SSRIs, SNRIs, and benzodiazepines in adults with anxiety disorders. Response was modeled for the standardized change in anxiety using Bayesian hierarchical models. Across 122 trials (N=15,760), SSRIs, SNRIs, and benzodiazepines produced significant improvement in anxiety compared to placebo. Benzodiazepines produced faster improvement by the first week of treatment (p<0.001). By week 8, the response for benzodiazepines and SSRIs (p=0.103) and SNRIs (p=0.911) did not differ nor did SSRIs and SNRIs differ (p=0.057), although for patients with generalized anxiety disorder (GAD), the benzodiazepines produced greater improvement than SNRIs at week 8 (difference-12.42, CrI: -25.05 to -0.78, p=0.037). Medication response was similar across anxiety disorders except for benzodiazepines, which produced greater improvement over the first 4weeks compared to SSRIs and SNRIs in panic disorder. For SSRIs and SNRIs, women improved more than men, and for benzodiazepines, older patients improved more compared to younger patients. Finally, placebo response plateaued by week 4 of treatment, and, at week 8, social anxiety disorder trials had lower placebo response compared to other anxiety disorders. Benzodiazepines show early improvement compared to SSRIs and SNRIs. However, by week 8, all treatments yield similar results. Patient characteristics influence the improvement trajectory and magnitude, suggesting potential for personalized medication selection.

Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression.

There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.

Brain-Hazardous Medications and Potential Subadequate Antidepressant Dosing in Older Surgical Patients Receiving Home Antidepressants: An Observational Study of a Large US Health System.

Older surgical patients with depression often experience poor postoperative outcomes. Poor outcomes may stem from brain-hazardous medications and subadequate antidepressant dosing. This was a retrospective, observational cohort study covering the period between January 1, 2021 and December 31, 2021. Patients ≥60 years of age who underwent inpatient surgery and had an overnight stay at an integrated academic health care system comprising 14 hospitals were eligible. We analyzed the prevalence of home central nervous system (CNS)-active potentially inappropriate medication (PIM) and potential subadequate antidepressant dosing in older surgical patients receiving home antidepressants. Univariable and multivariable regression models were used to identify factors associated with home CNS-active PIM prescribing and potential subadequate antidepressant dosing. Additionally, outcomes were compared among patients receiving and not receiving CNS-active PIMs and patients receiving and not receiving subadequate antidepressant dosing. A total of 8031 patients were included in this study (47% female, mean age = 70 years) of whom 2087 (26%) were prescribed antidepressants. Roughly one-half (49%, 95% confidence interval [CI], 46.5-50.1) of patients receiving home antidepressants were also receiving ≥1 CNS-active PIM and 29% (95% CI, 27.0-29.3) were receiving a potential subadequate dose. Factors associated with an increased likelihood of receiving a home CNS-active PIM included female sex (adjusted odds ratio [aOR], 1.46), anxiety (aOR, 2.43), asthma or chronic obstructive pulmonary disease (aOR, 1.39), and serotonin-norepinephrine reuptake inhibitor use (aOR, 1.54). Patients aged ≥75 years (aOR, 1.57), black race (aOR, 1.48) and those with congestive heart failure (aOR, 1.33) were more likely to be prescribed a potential subadequate antidepressant dose. Patients receiving potential subadequate antidepressant doses were discharged home less often (64% vs 73%), had a longer hospital length of stay (9 days vs 7 days), and a higher mortality rate (18% vs 10%) compared to patients receiving adequate home antidepressant doses (P-value for all <0.01). No differences in these outcomes were found among patients receiving home antidepressants with or without CNS-active PIMs. Older surgical patients receiving antidepressants are frequently prescribed brain-hazardous medications and potentially subadequate antidepressant doses. Those receiving subadequate antidepressant doses may be at risk for worse postoperative outcomes compared to patients receiving adequate doses. The role of preoperative medication optimization to improve outcomes for older surgical patients should be evaluated.

Duloxetine: An update

Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), has established itself as a versatile therapeutic agent across a spectrum of psychiatric and neurological disorders. The objective of this article is to update the pharmacological properties of duloxetine. To this end, a review was carried out on the pharmacology, clinical efficacy, safety and tolerability of duloxetine, focusing on its application in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain, fibromyalgia and musculoskeletal pain. chronic. Comparative analyzes highlight the relative effectiveness of duloxetine versus other antidepressants and its unique advantage in managing conditions with overlapping mood and pain symptoms. Safety profiles and pharmacological interactions, particularly with NSAIDs and tamoxifen, highlight the importance of personalized treatment plans and vigilant monitoring. The review concludes with an assessment of the clinical utility of duloxetine, emphasizing individual patient assessment to maximize therapeutic outcomes while minimizing risks. Future research directions are suggested to further delineate the role of duloxetine in treatment algorithms and explore potential new indications.

The anti-inflammatory effect of acupuncture on peripheral inflammatory cytokines in patients with major depressive disorder: A systematic review and meta-analysis

There is robust evidence that inflammation is closely associated with major depressive disorder (MDD). The antidepressant effect of acupuncture has been associated with favorable changes in peripheral levels of inflammatory cytokines. However, the findings of these studies were not consistent. This systematic review and meta-analysis were performed to explore the peripheral inflammatory cytokines of acupuncture in treating MDD. The study protocol was registered at PROSPERO, CRD42021289207. We conducted a systematic search for eligible randomized controlled trials (RCTs) that reported acupuncture as an intervention for patients with MDD. The outcome of interest was changes in inflammatory cytokine levels measured before and after the intervention. We searched electronic databases including PubMed, Embase, Cochrane, SinoMed, Wanfang, China National Knowledge Infrastructure (CNKI), and Chongqing VIP (CQVIP). Nine studies including 848 patients were eligible and included. The findings from two studies suggest that acupuncture may lead to changes in inflammatory cytokine levels, irrespective of comparisons with sham acupuncture or Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). While the small sample size, no firm conclusions can be drawn yet. Compared with SSRIs/SNRIs alone, the pooled effect estimation indicates acupuncture combined with SSRIs/SNRIs decreased levels of pro-inflammatory cytokines IL-6, TNF-α and IFN-γ, and elevated levels of anti-inflammatory cytokines IL-4 and IL-10. This study demonstrates that acupuncture appears to have an efficacy in producing anti-inflammatory effects in individuals with MDD.

Multiplexed quantification of venlafaxine and metabolites in human plasma by liquid chromatography-tandem mass spectrometry

BackgroundVenlafaxine (VEN) and its O-demethylated metabolite, O-desmethylvenlafaxine (ODV), are commonly prescribed serotonin-norepinephrine reuptake inhibitors, approved for the treatment of depression and anxiety. Both are metabolized to inactive metabolites via cytochrome P450 enzymes. While previous studies have focused on quantifying VEN and ODV, bioanalytical methods for the simultaneous measurement of all metabolites are needed to fully characterize the pharmacology of VEN and ODV. MethodsK2EDTA plasma was spiked with VEN, ODV, N-desmethylvenlafaxine (NDV), N,O-didesmethylvenlafaxine (NODDV), and N,N-didesmethylvenlafaxine (NNDDV). Drugs and metabolites were extracted via protein precipitation and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The multiplexed assay was validated in accordance with regulatory recommendations, and evaluated in remnant plasma samples from persons prescribed venlafaxine. ResultsThe analytical measuring range for venlafaxine and all four metabolites was 5–800 ng/mL. Standard curves were generated via weighted quadratic (NNDDV) or linear (VEN, ODV, NDV, NODDV) regression of calibrators. Inter-assay imprecision was between 1.9–9.3% for all levels of all analytes. Minor matrix effects were observed, and both recovery efficiency and process efficiency were >96% for all analytes. All other assay validation assessments met acceptance criteria. Drug concentrations measured from remnant plasma specimens obtained from patients with current venlafaxine prescriptions (37.5–450 mg/day) yielded NDDV, NDV, and NODDV metabolite concentrations in 6/21, 14/21, and 20/21 samples, respectively. The ratio of active to inactive analytes ranged from 0.74 to 14.5, with a median of 6.39. ConclusionsAn efficient and accurate LC-MS/MS method was developed and validated for the quantification of VEN, ODV, and all three inactive metabolites in plasma. The assay met all acceptance criteria, and may be used in future studies of the pharmacokinetics of these drugs.

Post-Stroke Depression in Older Adults: An Overview.

Detailed data on post-stroke depression (PSD) in older adults are limited in spite of the high vulnerability of this population to stroke. In fact, PSD prevalence in older adults ranges from 16.0 to 43.9%; however, timing and instruments of evaluation often differ significantly across all available studies. The etiology, genetic and inflammatory factors, as well as structural brain alterations, are claimed as part of a multifaceted mechanism of action in PSD onset. Thus, the aim of this narrative review was to further elaborate on the prevalence, etiology, diagnosis, consequences and treatment of PSD in older adults. The consequences of PSD in older adults may be devastating, including a poor functional outcome after rehabilitation and lower medication adherence. In addition, lower quality of life and reduced social participation, higher risk of new stroke, rehospitalization, and mortality have been reported. In this scenario, treating PSD represents a crucial step to prevent these complications. Both pharmacological and non-pharmacological therapies are currently available. The pharmacological treatment utilizes antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TAs) and new multimodal antidepressants (NMAs). Non-pharmacological therapies include psychological interventions and non-invasive brain stimulation techniques, while excluding drug administration. In the general population experiencing PSD, SSRIs (sertraline in particular) are the most prescribed, whereas the combination of antidepressants and psychotherapy is underused. Furthermore, about one-third of patients do not receive treatment for PSD. In regard to older adults with PSD, the possibility of more adverse effects or contraindications to antidepressant prescription due to comorbidities may limit the therapeutic window. Although drugs such as citalopram, escitalopram, sertraline, venlafaxine, and vortioxetine are usually well tolerated by older patients with PSD, the few randomized controlled trials (RCTs) specifically considering older adults with PSD have been conducted with fluoxetine, fluvoxamine, reboxetine, citalopram and nortriptyline, often with very small patient samples. Furthermore, data regarding the results of non-pharmacological therapies are scarce. High-quality RCTs recruiting large samples of older adults are needed in order to better manage PSD in this population. In addition, adequate screening and diagnosis instruments, with reliable timing of evaluation, should be applied.

Pharmacokinetics and Pharmacodynamics: A Comprehensive Analysis of the Absorption, Distribution, Metabolism, and Excretion of Psychiatric Drugs.

The two main classifications of antidepressant medications are selective norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). Out of the available choices, selective serotonin reuptake inhibitors (SSRIs) have emerged as the most commonly prescribed option. The class demonstrates a greater degree of diversity in its structural characteristics in contrast to its neurochemical effects. Nevertheless, it is important to acknowledge that the chemical composition of a drug within this specific class does not carry substantial significance in the selection process. A comprehensive analysis of the pharmacodynamic and pharmacodynamic properties of antidepressant drugs proves advantageous for clinicians and managed care providers responsible for selecting preferred selective serotonin reuptake inhibitors (SSRIs) from a roster of authorized medications. The physicochemical characteristics, which possess considerable significance, are frequently disregarded except during the drug development stage. Pharmacodynamic properties refer to the physiological and biochemical effects that drugs exert on the human body. It is noteworthy that the inclusion of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in a comprehensive depression management protocol may demonstrate enhanced effectiveness in clinical environments as opposed to controlled trials.

The pathobiology of depression in Huntington's disease: an unresolved puzzle.

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic-pituitary-adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

Effects of The Antidepressant Venlafaxine on The Expression of Peroxiredoxin-3 and Peroxiredoxin-5 Against LPS-induced Oxidative Stress in SHSY-5Y Neurons.

The main objective of this study was to examine the potential neuroprotective properties of venlafaxine, an antidepressant belonging to the serotonin-norepinephrine reuptake inhibitor class. Furthermore, it provides a novel insight into how venlafaxine might interact with peroxiredoxin-3 and -5 enzymes (PRDX-3 and PRDX-5), pivotal cellular antioxidant defence system components. For this purpose, human neuroblastoma (SHSY-5Y) cells were pretreated with venlafaxine (0-100 µM) for 12 h, followed by a 4 h LPS exposure (1 µg/mL) to induce oxidative stress. Cell viability was determined by MTT assay, and ROS generation was assessed by DCFH-DA assay. Protein and mRNA expression levels of PRDX-3 and PRDX-5 were determined by immunoblotting and RT-PCR, respectively. Based on the results obtained, it was found that the venlafaxine pre-treatment led to a notable reduction in intracellular ROS accumulation induced by LPS when compared to the control group (p&lt; 0.05). In the same manner, it was observed that venlafaxine pre-treatment altered LPS-induced PRDX-3 and PRDX-5 expression in neuronal cells (p&lt; 0.05). Our findings indicate the involvement of multifunctional PRDX-3 and PRDX-5 enzymes in the antioxidant effect of venlafaxine and suggest that further investigations into this pathway could provide valuable therapeutic contributions.

Patient journey of civilian adults diagnosed with posttraumatic stress disorder—A chart review study

Objective To assess the journey of individuals from experiencing a traumatic event through onset of symptoms, diagnosis, and treatment of posttraumatic stress disorder (PTSD). Methods Patient- and psychiatrist-level data was collected (02/2022–05/2022) from psychiatrists who treated ≥1 civilian adult diagnosed with PTSD. Eligible charts covered civilian adults diagnosed with PTSD (2016–2020), receiving ≥1 PTSD-related treatment (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], atypical antipsychotics [AAs]), and having ≥1 medical visit in the last 12 months. Collected information included clinical and treatment characteristics surrounding the PTSD diagnosis. Results A total of 273 psychiatrists contributed data on 687 patients with PTSD (average age 36.1; 60.4% female). On average, the traumatic event and symptom onset occurred 8.7 years and 6.5 years prior to PTSD diagnosis, respectively. In the 6 months before diagnosis, 88.9% of patients had received a PTSD-related treatment. At time of diagnosis, 87.8% of patients had intrusion symptoms and 78.9% had alterations in cognition/mood; 41.2% had depressive disorder and 38.7% had anxiety. Diagnosis prompted treatment changes for 79.3% of patients, receiving treatment within 1.9 months on average, often with a first-line SSRI as either monotherapy (52.8%) or combination (24.9%). At the end of the 24-month study period, 34.4% of patients achieved psychiatrist-recorded remission. A total of 23.0% of psychiatrists expressed dissatisfaction with approved PTSD treatments, with 88.3% at least somewhat likely to prescribe AAs despite lack of FDA approval. Conclusion PTSD presents heterogeneously, with an extensive journey from trauma to diagnosis with low remission rates and limited treatment options.

Pain management considerations in patients living with both pain syndromes and cardiovascular diseases and disorders.

Concomitant pain syndromes and cardiovascular disease (CVD) and disorders are associated with significant morbidity, impaired quality of life, and neuropsychiatric disorders. There is an interplay between the mechanisms of pathophysiology of both CVD and pain syndromes. Patients with CVD (and/or disorders) as well as pain syndromes have an increased propensity for drug-drug/disease interactions. Therefore, an understanding of how to use pharmacotherapy to treat pain syndromes, in the context of patients who have diagnoses of CVD and/or disorders, is paramount to patients' success in achieving adequate pain control and appropriately managing CVD and/or disorders, all while decreasing the risk of adverse events (AEs) both from pharmacotherapy to treat pain and CVD (and/or disorders). Based on the appraisal of literature and authors' clinical expertise, it was determined that gabapentinoids, opioids, skeletal muscle relaxants, tricyclic antidepressants, clonidine, serotonin norepinephrine-reuptake inhibitors, dronabinol, carbamazepine, second-generation antipsychotics, non-steroidal anti-inflammatory drugs, aspirin, corticosteroids, and topical anesthetics have the most evidence for use in patients with CVD and/or disorders. However, the literature surrounding the use of pharmacotherapy for pain management is limited to retrospective studies and there is a lack of well-designed, prospective, randomized trials; this also includes head-to-head comparator studies. Unlike many CVD-related pharmacotherapy studies, data studying pain management in patients with CVD lacks standardized outcomes that are consistent among the pool of data. Overall, the decision to prescribe specific pain management therapies in patients with CVD and/or disorders should include assessment of pain severity, type of pain, drug-drug/disease interactions, adjuvant therapies required, and the risk or presence of AEs.

Risk of abnormal uterine bleeding associated with high-affinity compared with low-affinity serotonin and norepinephrine reuptake inhibitors

BackgroundConcerns have been raised about the potential association between selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) and the risk of abnormal uterine bleeding (AUB), which may be influenced by the affinity of SSRIs/SNRIs for serotonin transporter. Thus, we assessed whether SSRIs/SNRIs with high-affinity for serotonin transporter are associated with AUB compared to SSRIs/SNRIs with low-affinity in non-pregnant women. MethodsUsing the UK Clinical Practice Research Datalink, we identified a cohort of women aged 15–24 years, newly prescribed a high- or low-affinity SSRI/SNRI between 1990 and 2019. Confounding was addressed using standardized morbidity ratio weighting. We used weighted Cox proportional hazards models to estimate the hazard ratio (HR) and 95 % confidence interval (CI) of AUB associated with high-affinity compared with low-affinity SSRIs/SNRIs. We assessed the risk of anemia as a secondary outcome. ResultsThe cohort included 156,307 users of high-affinity SSRIs/SNRIs and 102,631 users of low-affinity SSRIs/SNRIs. High-affinity SSRIs/SNRIs were not associated with an increased risk of AUB compared with low-affinity SSRIs/SNRIs (incidence rates: 46.3 versus 42.4 per 1000 person-years, respectively; HR 1.01, 95 % CI 0.93–1.09). Duration of use, age, and comorbidities did not modify the risk. However, high-affinity SSRIs/SNRIs were associated with an increased risk of anemia (HR 1.29, 95 % CI 1.04–1.61) compared with low-affinity SSRIs/SNRIs. LimitationsResidual confounding may still be present. ConclusionsThe risk of AUB did not differ between high- and low-affinity SSRIs/SNRIs. However, the potential risk of anemia suggests the need for monitoring and further investigation of the risk of AUB with these medications.

Brazilian Psychiatric Association guidelines for the treatment of Social Anxiety Disorder.

Social anxiety disorder (SAD) is one of the most prevalent anxiety disorders, often not well recognized. In most of the cases, SAD follows an unremitted and chronic course, affecting several areas of the individual functioning (i.e.: relationship, academic, work). Due to its relevance, there is a need for guideline-based treatments for SAD treatment adapted to the Brazilian social and economic reality. A systematic review was produced by our group assessing several treatment modalities for SAD. The Medical Subject Headings term used was Social Anxiety Disorder or Social Phobia. PubMed, Cochrane, Scielo, ClinicalTrials.gov were searched resulting in 438 articles screened, of which 20 were selected. Selective serotonin reuptake inhibitors are considered first line choices for the treatment of SAD, with great effects and a large database of evidence. Monoamine oxidase inhibitors (MAOIs), benzodiazepines and the anticonvulsants pregabalin and gabapentin are also effective. The serotonin noradrenaline reuptake inhibitor (SNRI) venlafaxine shows divergent results. With regards to psychological interventions, robust data offered evidence for cognitive behavioral therapy (CBT) as a first line option (individual, group and internet delivered). Psychodynamic psychotherapy, exposure and social skills therapy, self-help (with and without support) therapies, cognitive bias modification, virtual reality exposure therapy and mindfulness-based therapy are also effective techniques. Compared to pharmacological agents, psychological interventions are better tolerated and show evidence of long-term benefits. Patient's access to treatments (considering the Brazilian socioeconomic context), adherence, response rates (short and long-term treatment) and side effects must be considered when choosing the best strategy for the treatment of SAD.

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.

Duloxetine enhances the sensitivity of non-small cell lung cancer cells to EGFR inhibitors by REDD1-induced mTORC1/S6K1 suppression.

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been effective targeted therapies for non-small cell lung cancer (NSCLC), most advanced NSCLC inevitably develop resistance to these therapies. Combination therapies emerge as valuable approach to preventing, delaying, or overcoming disease progression. Duloxetine, an antidepressant known as a serotonin-noradrenaline reuptake inhibitor, is commonly prescribed for the treatment of chemotherapy-induced peripheral neuropathy. In the present study, we investigated the combined effects of duloxetine and EGFR-TKIs and their possible mechanism in NSCLC cells. Compared with either monotherapy, the combination of duloxetine and EGFR-TKIs leads to synergistic cell death. Mechanistically, duloxetine suppresses 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) activity through mechanistic target of rapamycin complex 1 (mTORC1), and this effect is associated with the synergistic induction of cell death of duloxetine combined with EGFR-TKIs. More importantly, activating transcription factor 4 (ATF4)-induced regulated in development and DNA damage response 1 (REDD1) is responsible for the suppression of mTORC1/S6K1 activation. Additionally, we found that the combination effect was significantly attenuated in REDD1 knockout NSCLC cells. Taken together, our findings reveal that the ATF4/REDD1/mTORC1/S6K1 signaling axis, as a novel mechanism, is responsible for the synergistic therapeutic effect of duloxetine with EGFR-TKIs. These results suggest that combining EGFR-TKIs with duloxetine appears to be a promising way to improve EGFR-TKI efficacy against NSCLC.

Non-opioid psychiatric medications for chronic pain: systematic review and meta-analysis.

The escalating number of deaths related to opioid usage has intensified the pursuit of non-opioid alternatives for managing chronic pain. It's often observed that psychiatric comorbidities coexist in patients suffering from chronic pain. There are a variety of psychotropic medications that have demonstrated effectiveness in treating both psychiatric symptoms and pain. This systematic review and meta-analysis aim to assess the effectiveness of various psychiatric drugs in managing specific types of chronic pain, including fibromyalgia, neuropathic pain, and chronic low back pain. A comprehensive search of five major databases was conducted through February 2023 to identify randomized controlled trials (RCTs) that met our inclusion criteria, focusing on outpatients Over 18 years of age with chronic pain. The study assessed the effectiveness of duloxetine, mirogabalin, pregabalin, gabapentin, and tricyclic antidepressants (TCAs), including serotonin-norepinephrine reuptake inhibitors (SNRIs), across various chronic pain conditions such as fibromyalgia, neuropathic pain, and chronic low back pain. The primary outcome measures included pain reduction, improvement in function, and quality of life. Of the 29 RCTs in the systematic review, 20 studies qualified for the meta-analysis. The analysis was stratified by pain type and treatment duration (short-term ≤14 weeks vs. long-term >14 weeks), using Hedge's g standardized mean differences and a random-effects model, along with sensitivity and subgroup analyses. The overall short-term intervention effect across all studies was significant (SMD -1.45, 95% CI -2.15 to -0.75, p < 0.001), with considerable heterogeneity (I2 = 99%). For fibromyalgia, both duloxetine and mirogabalin demonstrated substantial efficacy with SMDs of -2.42 (95% CI -3.67 to -1.18, p < 0.0001) and -2.10 (95% CI -3.28 to -0.92, p = 0.0005), respectively. Conversely, treatments for neuropathic pain and chronic low back pain, including those with amitriptyline and desipramine, did not show significant benefits. The effectiveness of gabapentin could not be conclusively determined due to limited representation in the data. Additionally, no consistent long-term benefits were observed for any of the medications. While the results of this study underscore the importance of exploring non-opioid alternatives for chronic pain management, particularly in light of the opioid crisis, it is crucial to interpret the findings carefully. Our analysis suggests that certain psychiatric medications, such Duloxetine and mirogabalin demonstrated significant short-term efficacy in fibromyalgia patients. However, their effectiveness in treating neuropathic pain and chronic low back pain was not statistically significant. Additionally, the effectiveness of gabapentin and other medications, such as pregabalin for neuropathic pain, could not be conclusively determined due to limited data and high study heterogeneity. No consistent long-term benefits were observed for any of the drugs studied, raising questions about their sustained efficacy in chronic pain management. These findings highlight the need for further research to understand better the role of psychiatric medications in managing specific chronic pain conditions without prematurely concluding that they are ineffective or unsuitable for these purposes.

Treatment of fibromyalgia among patients with mastalgia and fibromyalgia improved mastalgia.

The aim of this study is to examine the effect of fibromyalgia (FM) treatment on mastalgia by performing fibromyalgia screening in patients who applied for mastalgia and whose underlying cause could not be found. Patients who applied to Kocaeli University General Surgery Outpatient Clinic between November 2017 and November 2020 with breast pain were included (n=120). Patients without cancer, systemic disease, previous breast surgery, and breast mass larger than 3 cm (n=30) were referred to the Physical Therapy and Rehabilitation Outpatient Clinic. A total of 13 patients (43%) were diagnosed with FMS. Twelve of them were given selective serotonin-noradrenaline reuptake inhibitor (duloxetine) treatment for 3 months. Turkish version of the Short Form - 36 (SF-36) quality of life scores, Visual Analog Scale (VAS), Cardiff breast pain score before and after treatment were compared. The remaining 17 patients were followed as only mastalgia. Patients with fibromyalgia and mastalgia had similar demographic results. At the end of the 3rd month, the complaints of breast pain completely regressed in all of the patients. Statistically significant changes were detected in VAS score, the number of trigger points, and SF-36 quality of life scores, Cardiff breast pain score after duloxetine treatment. In the presence of unexplained mastalgia, fibromyalgia should be kept in mind. Duloxetine treatment improved the breast pain and quality of life in patients with mastalgia and fibromyalgia.

Drugs for depressionr.

A selective serotonin reuptake inhibitor (SSRI) is generally used for initial treatment of major depressive disorder (MDD). A serotonin-norepinephrine reuptake inhibitor (SNRI), bupropion (Wellbutrin SR, and others), and mirtazapine (Remeron, and others) are reasonable alternatives. Improvement in symptoms can occur within the first two weeks of treatment with these drugs, but a substantial benefit may not be achieved for 4-8 weeks.