Norepinephrine Reuptake Inhibitor Research Articles

P209. Combination of Venlafaxine and Brexpiprazole Induces an Early Enhancement in Dopamine Neurons Activity

The addition of a low dose of dopamine (DA) / serotonin1A (5-HT1A) partial agonists, including brexpiprazole (BREX), to selective 5-HT reuptake inhibitors (SSRI) or selective norepinephrine reuptake inhibitors (SNRI), like venlafaxine (VEN) is often used to successfully treat some treatment-resistant major depressive disorder (MDD) patients. Administration of these partial agonists could counterbalance the attenuating actions of SSRIs/SNRIs on firing activity of catecholamine neurons, resulting in reversal of deficient DA and NE tone that could be of crucial importance in the treatment of MDD. This study investigated whether BREX combined with VEN can induce a change in DA neurons activity that is initially not induced by VEN only.

Myricitrin exhibits antidepressant-like effects and reduces IL-6 hippocampal levels in the chronic mild stress model

The flavonoid myricitrin showed an antidepressant-like effect in the tail suspension test and increased hippocampal neurogenesis, as well as demonstrating anti-inflammatory effects. Interestingly, inflammation has been linked to depression, and anti-inflammatory drugs showed promising results as antidepressant-like drugs. Thus, the present study evaluated the effects of myricitrin in the chronic mild stress (CMS) model, a translational and valid animal model of depression, using the mini-experiment design to improve the reproducibility of the findings. The sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were the readouts of depressive-like phenotypes induced by CMS. Relative adrenal weight was employed as an index of the hypothalamus–pituitary–adrenal (HPA) axis activation. Interleukin (IL)−6 and tumor necrosis factor (TNF)-alpha levels were measured in the hippocampus. Myricitrin (10 mg/kg, intraperitoneally, for 14 days) reversed depressive-like behaviors induced by CMS (increased immobility in the FST, the TST and anhedonia), as well as decreased adrenal hypertrophy and hippocampal levels of IL-6 in stressed mice. Similar results were observed by imipramine (20 mg/kg, intraperitoneally, for 14 days), a serotonin and norepinephrine reuptake inhibitor (positive control). A significant correlation was observed between immobility time in the TST, and hippocampal IL-6 levels. Hippocampal TNF-α levels were not affected by CMS or drug treatment. In conclusion, myricitrin exhibited an antidepressant-like profile in CMS, and this effect may be associated with its anti-inflammatory activity.

Investigational synthetic neuroactive steroid zuranolone in treatment of major depressive disorder with peripartum onset

Major depressive disorder with peripartum onset or peripartum depression is a common condition experienced by a large proportion of women and to some extent even in men. The current treatment strategies involve the use of conventional pharmacotherapeutic classes of drugs like selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and psychotherapy methods in the management of this condition. In this article, we try to review and evaluate the pathophysiology of the condition along with the safety and efficacy of the novel investigational therapeutic drug zuranolone, which is a synthetic neuroactive steroid (NAS) that has shown promise in clinical trials for the management of conditions like major depressive disorder, peripartum depression and bipolar disorder. The synthetic NAS zuranolone is an orally bioavailable positive allosteric modulator of the gamma amino butyric acid (GABAA) receptor, which can regulate the action of the GABAergic pathway implicated in many depressive episodes and also affect the normal functioning of the hypothalmo pituitary-adrenal (HPA) axis which is the core pathophysiological cause behind major depressive disorder with peripartum onset.

Pharmacological approach to neuropathic pain: past, present and future

Neuropathic pain (NP) is difficult to treat due to the heterogeneity of causes, symptoms and underlying mechanisms. It constitutes a great medical need that is not covered, and has a high number of therapeutic failures in recent randomized clinical trials. This narrative review presents an update on the pharmacological treatment of NP with emphasis on the new published clinical guidelines, new drugs in development, and the new challenges that arise in the therapeutic management of this entity. First-line drugs proposed include tricyclic antidepressants (particularly amitriptyline), serotonin and norepinephrine reuptake inhibitors (particularly duloxetine), pregabalin, and gabapentin. However, the latest recommendations are still relevant and the most recent clinical studies even question the role of pregabalin as a first-line treatment. Therefore, we consider that periodic updates of the clinical guidelines in NP are necessary to better guide our daily clinical practice and rationalize the use of all available therapeutic options. Furthermore, the expansion of knowledge in NP has generated a series of challenges, such as the development of new drugs based on pathophysiological mechanisms investigated in animals, and the development of optimal therapeutic approaches in clinical trials, based more on personalized than etiological approaches.

Serotonin-norepinephrine reuptake inhibitor antidepressant effects on regional connectivity of the thalamus in persistent depressive disorder: evidence from two randomized, double-blind, placebo-controlled clinical trials.

Previous neuroimaging studies have shown that serotonin–norepinephrine reuptake inhibitor antidepressants alter functional activity in large expanses of brain regions. However, it is not clear how these regions are systemically organized on a connectome level with specific topological properties, which may be crucial to revealing neural mechanisms underlying serotonin–norepinephrine reuptake inhibitor treatment of persistent depressive disorder. To investigate the effect of serotonin–norepinephrine reuptake inhibitor antidepressants on brain functional connectome reconfiguration in persistent depressive disorder and whether this reconfiguration promotes the improvement of clinical symptoms, we combined resting-state functional magnetic resonance imaging (fMRI) scans acquired in two randomized, double-blind, placebo-controlled trial studies of serotonin–norepinephrine reuptake inhibitor antidepressant treatment of patients with persistent depressive disorder. One was a randomized, double-blind, placebo-controlled trial of 10-week duloxetine medication treatment, which included 17 patients in duloxetine group and 17 patients in placebo group (ClinicalTrials.gov Identifier: NCT00360724); the other one was a randomized, double-blind, placebo-controlled trial of 12-week desvenlafaxine medication treatment, which included 16 patients in desvenlafaxine group and 15 patients in placebo group (ClinicalTrials.gov Identifier: NCT01537068). The 24-item Hamilton Depression Rating Scale was used to measure clinical symptoms, and graph theory was employed to examine serotonin–norepinephrine reuptake inhibitor antidepressant treatment effects on the topological properties of whole-brain functional connectome of patients with persistent depressive disorder. We adopted a hierarchical strategy to examine the topological property changes caused by serotonin–norepinephrine reuptake inhibitor antidepressant treatment, calculated their small-worldness, global integration, local segregation and nodal clustering coefficient in turn. Linear regression analysis was used to test associations of treatment, graph properties changes and clinical symptom response. Symptom scores were more significantly reduced after antidepressant than placebo administration (η2 = 0.18). There was a treatment-by-time effect that optimized the functional connectome in a small-world manner, with increased global integration and increased nodal clustering coefficient in the bilateral thalamus (left thalamus η2 = 0.21; right thalamus η2 = 0.23). The nodal clustering coefficient increment of the right thalamus (ratio = 29.86; 95% confidence interval, −4.007 to −0.207) partially mediated the relationship between treatment and symptom improvement, and symptom improvement partially mediated (ratio = 21.21; 95% confidence interval, 0.0243–0.444) the relationship between treatment and nodal clustering coefficient increments of the right thalamus. Our study may indicate a putative mutually reinforcing association between nodal clustering coefficient increment of the right thalamus and symptom improvement from serotonin–norepinephrine reuptake inhibitor antidepressant treatments with duloxetine or desvenlafaxine.

COVID-19 Outcomes: Does the Use of Psychotropic Drugs Make a Difference? Accumulating Evidence of a Beneficial Effect of Antidepressants-A Scoping Review.

Purpose/BackgroundStudies for repurposed drugs in severe acute respiratory syndrome coronavirus type 2–infected and coronavirus disease 2019 (COVID-19) patients are ongoing. According to preclinical research, antidepressants (ADs) might be useful in the treatment of COVID-19.Methods/ProceduresWe conducted a scoping review including clinical studies on AD effects on SARS-CoV-2 infection and COVID-19.Finding/ResultsAs of January 2, 2022, we found 14 clinical studies, which could be included into this review. Among them, there were 2 randomized, placebo-controlled studies and 2 prospective parallel-group studies about the efficacy/effectiveness and tolerability of fluvoxamine. The remaining studies were mainly retrospective studies considering COVID-19 hospital populations predominantly exposed to fluoxetine (N = 3), other selective serotonin reuptake inhibitors (SSRI), selective norepinephrine reuptake inhibitors (SNRI), and trazodone. The vast majority were hospital studies and assessed COVID-19 severity (morbidity) and mortality as primary endpoints. The only outpatient study (fluvoxamine) investigated the COVID-19–related hospitalization rate, and 1 psychiatric hospital study (SSRI, SNRI, trazodone) focused on the SARS-CoV-2 infection rate.Implications/ConclusionsAt present, the best evidence of an “anti–COVID-19” potential of ADs exists for fluvoxamine and, to a lesser extent, for fluoxetine. Preliminary evidence had found that patients exposed to SSRI or SNRI substance classes might have a reduced mortality risk and that trazodone might reduce SARS-CoV-2 infection rates. Three studies found no relevant influence of ADs on COVID-19 morbidity and mortality, and 1 study described increased mortality. The latter study, however, did not differentiate between psychotropic medication and ADs. Tricyclics and monoamine oxidase inhibitors are still absolute “dark zones” in COVID-19 research. Further controlled studies testing the effectiveness/efficacy and tolerability/safety (as well as the treatment timing and duration) of different AD substance classes in COVID-19 and post/long-COVID patients of various populations are warranted.

Therapeutic drug monitoring of atomoxetine in children and adolescents with attention-deficit/ hyperactivity disorder: a naturalistic study

The selective norepinephrine reuptake inhibitor atomoxetine is potentially among the first-line pharmacotherapy options for ADHD. Therapeutic drug monitoring (TDM) with the quantification and interpretation of atomoxetine serum concentrations is used to determine an individual dose followed by an optimal effectiveness and minimal side effects. The aim of this retrospective pharmacokinetic–pharmacodynamic analysis was to derive age-appropriate recommendations for the implementation of TDM to improve the efficacy and tolerability of atomoxetine in children and adolescents. Using the analytical method of high-performance liquid chromatography with UV detection, 94 serum concentrations of 74 patients between 6 and 21 years of age were determined. Therapeutic effectiveness and side effects were evaluated according to the categories “low”, “moderate”, and “significant”. As part of TDM, a time interval with maximum concentrations of 1–3 h after the administration of atomoxetine was determined for blood sampling. In this time interval, a significant correlation between the weight-normalized dose and the serum concentrations was found. The efficacy as well as the tolerability proved to be mainly moderate or significant. A preliminary therapeutic reference range was between 100 and 400 ng/ml. Naturalistic studies have limitations. Therefore, and due to a limited study population, the results have to be regarded as preliminary observations that must be confirmed in further studies. The preliminary therapeutic reference range for children and adolescents proved to be narrower than the reference range for adult patients. However, due to good efficacy and tolerability an exact reference range remained difficult to determine.

Design and synthesis of two Strychnidin‐oxiran‐naphthalenol derivatives and their theoretical evaluation as noradrenaline and serotonin reuptake inhibitors

AbstractSeveral agents have been used as biogenic amine reuptake inhibitors for depression such as imipramine, fluoxetine, reboxetine, and others; however, some of these drugs can produce some secondary effects such as tiredness and psychomotor retardation. Analyzing these data, the aim of this study was to synthesize two Strychnidin‐oxiran‐naphthalenol derivatives using some chemical tools. Besides, the theoretical interaction of Strychnin‐oxiran‐naphthalenol derivatives (compounds 7 and 8) as noradrenaline and serotonin reuptake inhibitors was evaluated using two proteins (1ieo and 5i6z) as theoretical models in a docking model. The results showed a good yielding to synthesis of compounds 7 and 8. Other data suggest that either compounds 7 or 8 could interact with both 1ieo and 5i6z proteins surface, this phenomenon may be translated as changes in the biological activity of norepinephrine and serotonin reuptake. Therefore, compounds 7 and 8 could be considered two good candidates as antidepressants agents.

Pediatric Psychopharmacology for Depressive and Anxiety Disorders.

Anxiety and depressive disorders are the most common psychiatric illnesses among children and adolescents. These disorders are associated with impairments in social, family, and educational functioning. This article summarizes the evidence base for psychopharmacologic interventions; the developmental pharmacology of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs); and pharmacokinetic and pharmacodynamic differences between youths and adults that call for differences in dosage and affect response and tolerability. The authors also review the efficacy and tolerability of SSRIs and SNRIs in children and adolescents with depressive and anxiety disorder diagnoses, as well as data related to duration of therapy and SSRI/SNRI discontinuation in this population. Taken together, the current evidence suggests that SSRIs are the first-line psychopharmacologic intervention for youths with depressive and anxiety disorders, with SNRIs having a more limited role. These medications are safe and well tolerated, although emerging data and developmental pharmacologic concepts may help clinicians to choose from available SSRIs and to improve the efficacy and tolerability of these medications in children and adolescents.

Opioid and Benzodiazepine Substitutes: Impact on Drug Overdose Mortality in Medicare Population

IntroductionGabapentinoids (GABAs) and serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs]/serotonin and norepinephrine reuptake inhibitors [SNRIs]) are increasingly being prescribed as potential substitutes to opioids and benzodiazepines (benzos), respectively, to treat co-occurring pain and anxiety disorders. The toxicities of these drug classes and their combinations are not well understood. MethodsWe conducted a matched case-control study using 2013-2016 Medicare files linked to the National Death Index. Cases were enrollees who died from drug overdose. Controls were enrollees who died from other causes. Cases and controls were matched on patient characteristics and prior chronic conditions. Possession of any opioids, GABAs, benzos, and SSRIs/SNRIs in the month prior to death was defined as drug use. Combination drug use was defined as possessing at least 2 types of these prescriptions for an overlapping period of at least 7 days in the month prior to death. ResultsAmong 4323 matches, benzo possession was associated with twice the risk for drug overdose death in cases vs controls. Compared with opioid-benzo co-prescribing, combinations involving SSRIs/SNRIs and opioids (or GABAs) were associated with decreased risk (adjusted odds ratio 0.55; 95% confidence interval, 0.44-0.69 for opioids and SSRIs/SNRIs; adjusted odds ratio 0.59; 95% confidence interval, 0.44-0.79 for GABAs and SSRIs/SNRIs). Fatal drug overdose risk was similar in users of GABA-opioid, GABA-benzo, and opioid-benzo combinations. ConclusionsBenzodiazepines, prescribed alone or in combination, were associated with an increased risk of drug overdose death. SSRIs/SNRIs were associated with lower risk of overdose death vs benzodiazepines. GABAs were not associated with decreased risk compared with opioids, raising concerns for GABAs’ perceived relative safety.

Glial cells as target for antidepressants in neuropathic pain

Abstract Several forms of chronic pain do not respond to the conventional analgesics, such as opioids, but can be treated with antidepressants, such as serotonin and noradrenalin reuptake inhibitors (SNRIs). Recent studies indicate that noradrenalin signalling is a key target for SNRI-induced analgesia in neuropathic pain. SNRIs inhibit chronic pain by blocking reuptake of noradrenalin and subsequent activation of adrenergic receptors on neurons in the dorsal horn of the spinal cord. However, in the nervous system, various subtypes of adrenergic receptors are highly expressed by astrocytes and microglial cells. Activation of these receptors on astrocytes engages complex intracellular signalling pathways and prevents inflammatory changes of microglia, which in turn can affect neuronal activity. Hence, SNRIs-induced modulations of the glial cell physiology can impact neural circuit functions and pain perception. In this review, we summarize our current knowledge on the impact of SNRIs on glial cells and in modulating chronic pain in experimental animal models.

Medications with Potential for Fetal Risk Prescribed to Veterans.

Background: Women service members of the past 20 years experienced high rates of traumatizing events resulting in pharmacological treatment. Post-military lives may include having children. Typically, Veterans Health Administration (VHA) patients' pregnancies are managed outside the VHA. This study examined medication exposures during pregnancy. Materials and Methods: The Center for Maternal and Infant Outcomes Research in Translation (COMFORT) study collected primary survey data and linked secondary health care data from the VHA from 2015 to 2021. Medication fills and covariates were extracted for three 9-month periods: preconception, pregnancy, and postpartum. Multiple regression assessed factors associated with use during pregnancy of selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI) or of non-recommended, potentially risky drugs, and of discontinuation of those medications from prepregnancy to pregnancy. Results: The cohort comprised 501 women-29% Black, 65% White, and 6% other races, of whom 63% had 50%-100% service-connected disability. During pregnancy, 36% had a pain-related disorder, 19% major depression, and 18% post-traumatic stress disorder. The median number of drug classes prescribed during pregnancy was 5. The use of SSRI/SNRI antidepressants dropped from 36% preconception to 26% during pregnancy including new starts; 15% discontinued SSRI/SNRI. Comorbidity predicted medication use. Depression predicted discontinuing SSRI/SNRI during pregnancy; no predictors of discontinuing potentially risky drugs were identified. Conclusions: Based on prescriptions filled within the VHA only-ignoring potential community-based fills-women veterans were prescribed numerous medications during pregnancy and discontinued antidepressants alarmingly. Veterans of childbearing potential should receive counseling about medication use before pregnancy occurs. Their non-VHA obstetricians and VHA providers should share information to optimize outcomes, reviewing medications as soon as pregnancy is detected as well as after pregnancy concludes.

Evaluation of visual reaction time in patients with fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) has previously been linked to cognitive dysfunction. The aim of this study was to compare visual reaction time (RT) between FMS patients and healthy subjects. The relationship was examined between RT and clinical parameters in FMS patients, and it was aimed to evaluate the effect of drugs used in the treatment of FMS on RT. A total of 112 FMS patients and 110 healthy volunteers were included in this cross-sectional research. Cognitive performance was evaluated with visual RT measurements. FMS patients were assessed using the Fibromyalgia impact questionnaire (FIQ), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS) and Pittsburgh Sleep Quality Index (PSQI). The drugs used in the treatment of FMS were recorded. Significantly prolonged visual RT measurements were detected in FMS patients (p < 0.001). There was no significant difference in RT measurements between the patients who did not use drugs and those who were treated with serotonin noradrenaline reuptake inhibitor, gabapentinoid and combination therapy (p > 0.05). RT was significantly correlated with FIQ, BDI and PSQI scores in FMS patients (rho: 0.290, p = 0.002 for FIQ; rho: 0.253, p = 0.007 for BDI and rho: 0.312, p = 0.001 for PSQI). No significant correlation was detected between RT scores and FSS values (p > 0.05). Visual RT measurements were seen to be deteriorated in FMS patients. As the disease severity, depression level, and sleep disturbance increased, so the impairment in visual RT values became more prominent. The drugs used in the FMS treatment did not influence the RT scores. Cognitive performance tests should be incorporated in the physical examination and follow-up courses of FMS patients.

Prolonged Post Traumatic Headache after Repetitive Sports Related Concussions

Background: Human and animal studies have shown evidence of pathological brain changes as well as increased cognitive dysfunction with repetitive injury. Case Presentation: We present a case of prolonged persistent post concussive symptoms after a mild concussion, in the setting of multiple prior concussions. In this case a 29-year-old man presented for a moderate persistent daily headache for one month after a minor injury due to a branch hitting his helmet while mountain biking. He had previously sustained one non-sports related concussion with loss of consciousness as well as at least two other sports related concussions in the past five years which caused one-to-two-week intervals of headaches and dizziness. At initial evaluation he reported persistent photosensitivity, difficulty working on screens, as well as intermittent lightheadedness, insomnia, irritability, anxiety, and anhedonia. Symptoms of headache completely resolved over the course of three months with serotonin norepinephrine reuptake inhibitors (SSRI) management, but he reported some persistent anxiety and depressive symptoms. Conclusion: This case report highlights the long-term impact as well as the need for more specific return to activity guidelines for patients with multiple prior concussions.

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice.

Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a “two-hit” stress mouse model. The “two-hit” stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the “two-hit” stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.

Psychological and Psychopharmacological Interventions in Psychocardiology

Patients with mental disorders have an increased risk to develop cardiovascular disease (CVD), and CVD are frequently comorbid with especially adjustment, anxiety and depressive disorders. Therefore, clinicians need to be aware of effective and safe psychological and pharmacological treatment strategies for patients with comorbid CVD and mental disorders. Cognitive behavioral therapy and third-wave of cognitive-behavioral therapy are effective for patients with CVD and mental disorders. Internet-based psychological treatments may also be considered. In more severe cases, psychopharmacological drugs are frequently used. Although generally well tolerated and efficacious, drug- and dose-dependent side effects require consideration. Among antidepressants, selective serotonin reuptake inhibitors, selective serotonin and noradrenalin reuptake inhibitors, and newer antidepressants, such as mirtazapine, bupropion, agomelatine, and vortioxetine, can be considered, while tricyclic antidepressants should be avoided due to their cardiac side effects. Mood stabilizers have been associated with arrhythmias, and some first- and second-generation antipsychotics can increase QTc and metabolic side effects, although substantial differences exist between drugs. Benzodiazepines are generally safe in patients with CVD when administered short-term, and may mitigate symptoms of acute coronary syndrome. Laboratory and ECG monitoring is always recommended in psychopharmacological drug-treated patients with CVD. Presence of a heart disease should not exclude patients from necessary interventions, but may require careful risk-benefit evaluations. Effectively and safely addressing mental disorders in patients with CVD helps to improve both conditions. Since CVD increase the risk for mental disorders and vice versa, care providers need to screen for these common comorbidities to comprehensively address the patients’ needs.

Association between selective serotonin and serotonin–noradrenaline reuptake inhibitor therapy and hematuria

Background Selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline reuptake inhibitors (SNRIs) are used as first-line treatment for many psychiatric diseases, especially major depressive disorder. However, an important side effect of these drugs is the risk of bleeding due to platelet dysfunction. The aim of this study was to determine the frequency of hematuria in patients using SSRI/SNRIs and to compare with a control group. Methods This study included patients who were followed up and treated with SSRI/SNRI in the psychiatric outpatient clinic of the Antalya Medical Park Hospital between 1 January 2021 and 31 March 2021 and a control group comprising patients who presented to the medical check-up outpatient clinic between the same dates. Complete urinalysis was performed for all patients and the results were compared between the groups. Results Each group included 100 patients with a female/male ratio of 1. The mean age was 41.45 ± 13.47 (16–74) years in the study group and 40.51 ± 13.75 (20–70) years in the control group (p = 0.519). Mean duration of SSRI/SNRI use in the study group was 13.35 ± 1.32 (1–64) months. The prevalence of hematuria was 17% in the SSRI/SNRI group and 6% in the control group (p = 0.015). All cases of hematuria were microscopic hematuria. Conclusion Hematuria is significantly more common in patients receiving SSRI/SNRI treatment. The use of SSRI/SNRI should also be taken into account when investigating the etiology of hematuria.

Depression and Long-Term Prescription Opioid Use and Opioid Use Disorder: Implications for Pain Management in Cancer.

Opinion statementPreventing depression in cancer patients on long-term opioid therapy should begin with depression screening before opioid initiation and repeated screening during treatment. In weighing the high morbidity of depression and opioid use disorder in patients with chronic cancer pain against a dearth of evidence-based therapies studied in this population, patients and clinicians are left to choose among imperfect but necessary treatment options. When possible, we advise engaging psychiatric and pain/palliative specialists through collaborative care models and recommending mindfulness and psychotherapy to all patients with significant depression alongside cancer pain. Medications for depression should be reserved for moderate to severe symptoms. We recommend escitalopram/citalopram or sertraline among selective serotonin reuptake inhibitors (SSRIs), or the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, or desvenlafaxine if patients have a significant component of neuropathic pain or fibromyalgia. Tricyclic antidepressants (TCAs) (consider nortriptyline or desipramine, which have better anticholinergic profiles) should be considered for patients who do not respond to or tolerate SSRI/SNRIs. Existing evidence is inadequate to definitively recommend methylphenidate or novel agents, such as ketamine or psilocybin, as adjunctive treatments for cancer-related depression and pain. Physicians who treat patients with cancer pain should utilize universal precautions to limit the risk of non-medical opioid use (non-medical opioid use). Patients should be screened for non-medical opioid use behaviors at initial consultation and at regular intervals during treatment using a non-judgmental approach that reduces stigma. Co-management with an addiction specialist may be indicated for patients at high risk of non-medical opioid use and opioid use disorder. Buprenorphine and methadone are indicated for the treatment of opioid use disorder, and while they have not been systematically studied for treatment of opioid use disorder in patients with cancer pain, they do provide analgesia for cancer pain. While an interdisciplinary team approach to manage psychological stress may be beneficial, this may not be possible for patients treated outside of comprehensive cancer centers.

A Clinical Review on Paroxetine and Emerging Therapies for the Treatment of Vasomotor Symptoms.

Most women experience vasomotor symptoms (VMS) during their menopausal transition. Menopausal hormone therapy (HT) is the most effective treatment for VMS, but some women choose not to use HT or have contraindications to using HT. Non-hormonal treatment options should be offered to these symptomatic menopausal women. Multiple large randomized controlled trials have demonstrated statistically significant reductions in hot flash severity and/or frequency with the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). To date, paroxetine mesylate remains the only non-hormonal treatment that has been approved by the United States Food and Drug Administration (FDA) for the management of moderate to severe postmenopausal vasomotor symptoms. Lower doses are needed to reduce VMS than those used to treat anxiety or depression, which is beneficial since side effects are typically dose dependent. The recommended dosage is 7.5 mg once daily at bedtime. Dose dependent side effects include nausea, fatigue, and dizziness. Knowing potential medication interactions is critical such as with medications that can lead to serotonin syndrome, concomitant use with monoamine oxidase inhibitors and being aware of p450 drug metabolism is essential for patients taking drugs that utilize the CYP2D6 enzyme for metabolism including tamoxifen. This review discusses in detail the available data supporting the use of paroxetine for the treatment of VMS, including side effects and considerations regarding prescribing. A discussion of other emerging treatments is included as well, including estetrol, oxybutynin and neurokinin 3 (NK3) receptor antagonists.

The Effects of Drugs on Behavior Maintained by Social Contact: Role of Monoamines in Social Reinforcement.

Drug use is highly concordant among members of adolescent and young adult peer groups. One potential explanation for this observation is that drugs may increase the reinforcing effects of social contact, leading to greater motivation to establish and maintain contact with other members of the peer group. Several classes of drugs, particularly drugs that increase synaptic dopamine, increase the reinforcing effects of contextual stimuli, but the extent to which these drugs enhance the reinforcing effects of social contact is not known. The purpose of this study was to determine the extent to which drugs that increase synaptic dopamine, norepinephrine, and serotonin enhance the positive reinforcing effects of social contact. To this end, male and female Long-Evans rats were pretreated with acute doses of the selective dopamine reuptake inhibitor, WIN-35,428, the selective norepinephrine reuptake inhibitor, atomoxetine, the selective serotonin reuptake inhibitor, fluoxetine, the non-selective monoamine reuptake inhibitor, cocaine, and the non-selective monoamine releasers d-amphetamine and (±)-MDMA. Ten minutes later, the positive reinforcing effects of 30-s access to a same-sex social partner was examined on a progressive ratio schedule of reinforcement. To determine whether the reinforcement-altering effects of these drugs were specific to the social stimulus, the reinforcing effects of a non-social stimulus (30-s access to an athletic sock of similar size and coloring as another rat) was determined in control subjects. WIN-35,428, d-amphetamine, and cocaine, but not atomoxetine, fluoxetine, or MDMA, dose-dependently increased breakpoints maintained by a social partner under conditions in which responding maintained by a non-social stimulus was not affected. These data indicate that increases in extracellular dopamine, but not extracellular norepinephrine or serotonin, increases the positive reinforcing effects of social contact in both male and female rats. These data also provide support for the hypothesis that some drugs with high abuse liability increase the motivation to establish and maintain contact with social peers.