Selective Norepinephrine Reuptake Research Articles

Adolescent stress differentially modifies dopamine and norepinephrine release in the medial prefrontal cortex of adult rats

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction.

Viloxazine Increases Cortical Serotonin Without Inhibiting Serotonin Reuptake at Doses Used to Treat ADHD

AbstractBackgroundMost FDA-approved ADHD treatments increase norepinephrine (NE) and dopamine (DA); however, our prior preclinical studies of the non-stimulant ADHD treatment viloxazine ER (Qelbree®) demonstrated that viloxazine also increases serotonin (5-HT). A prior microdialysis study showed increases in NE, DA, and 5-HT in the rat prefrontal cortex (PFC); however, the 50 mg/kg dose resulted in supratherapeutic plasma concentrations. Viloxazine is a moderate affinity selective NE reuptake inhibitor, structurally different than traditional SSRI antidepressants. Viloxazine has negligible activity at the serotonin reuptake transporter (SERT), suggesting viloxazine has a different mechanism of 5-HT PFC elevation than SSRIs. The current microdialysis study was undertaken to further characterize if viloxazine affects 5-HT and its 5-HIAA metabolite at therapeutically relevant plasma concentrations. Results are compared to similar microdialysis studies of SSRIs.MethodsRats were implanted with I-shaped microdialysis probes connected to a microperfusion pump, delivering artificial cerebrospinal fluid, in the PFC. After a 2-hour baseline period, viloxazine (1, 3, 10, or 30 mg/kg) was administered (ip). Dialysate samples were collected from the interstitial fluid (ISF) of the PFC before and after dosing. LC-MS/MS was used to determine the dialysate concentrations of viloxazine and viloxazine-induced changes in NE, 5-HT, and their respective metabolites, DHPG and 5-HIAA. Viloxazine plasma concentrations were also measured.Animal research was approved by the Institutional Animal Care and Use Committee and conducted in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals.ResultsViloxazine administration resulted in significant dose-dependent increases in ISF NE levels and corresponding decreases in DHPG (NE metabolite) at all doses tested, reflecting viloxazine’s activity as a NET inhibitor. Viloxazine treatment also resulted in a dose-dependent elevation of ISF 5-HT levels in the PFC. Of the doses tested, 30 mg/kg was found to be clinically relevant as it induced ISF concentrations approximating unbound plasma concentrations in pediatric ADHD patients. At this dose, 5-HT levels were significantly increased over baseline and higher than vehicle levels. Coincident changes in 5-HIAA concentrations were not observed, reaffirming viloxazine’s lack of activity as a SERT inhibitor.ConclusionViloxazine induced dose-dependent increases in NE and 5-HT in the PFC, a critical target region for ADHD therapies. At clinically relevant viloxazine plasma concentrations, 5-HT was increased in the PFC. Unlike SSRIs, which correspondingly decrease the 5-HT metabolite in the PFC (indicating serotonin reuptake inhibition), viloxazine did not affect 5-HIAA levels. Thus, viloxazine increases cortical 5-HT levels by a different mechanism than SSRIs. Whether 5-HT effects aid in viloxazine therapeutic efficacy in ADHD is yet unknown.FundingSupernus Pharmaceuticals, Inc.

Antidepressants

Antidepressant medications have numerous clinical uses in the field of psychiatry. There are many antidepressant classes, with the selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors being commonly used in clinical practice for depression and anxiety. Although these medications are effective, complete clinical effect is not rapid and full relief of symptoms can take more than a month. However, side effects with antidepressants can be expected to occur upon initiation of treatment and may lead to patient nonadherence. Education and appropriate patient counseling are necessary to assure that the therapeutic effects of medications are maximized. Treatment with antidepressants should be tailored to patient-specific criteria. This review contains 1 figure, 4 tables and 43 references Key Words: antidepressants, FDA-approved, obsessive-compulsive disorder, monoamine oxidase, MAOIs, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants.

Transplacental transfer of venlafaxine evaluated by ex vivo perfusion.

Depression is frequent among pregnant women and decision for treatment with antidepressants needs careful consideration of risks for the fetus. Since data regarding fetal antidepressant exposure are rare, we aimed to evaluate transplacental transfer of venlafaxine, a selective norepinephrine reuptake inhibitor. Ex vivo human placental perfusion experiments were conducted in double closed set-up. Venlafaxine (18.1±2.1μg/L) was offered in maternal circuit and maternal-to-fetal transfer was monitored over a period of 3h. Venlafaxin and O-desmethylvenlafaxine concentrations were determined by HPLC-MS in maternal and fetal perfusion medium. We observed maternal-to-fetal transfer of venlafaxine within 5min perfusion. The concentration equilibrium was approximated between maternal (7.5±0.5μg/L) and fetal (6.5±0.6μg/L) compartment at time point 180min, which corresponds to a fetal-maternal (FM) ratio of 0.89. Our results are comparable with in vivo data from an observational study which emphasizes that the ex vivo placental perfusion model is suitable for systematic evaluation of fetal antidepressant exposure.

Depression treatment in women and men with bipolar affective disorder: a comparative study

Objective: to compare depression treatment efficacy with and without antidepressants (ADs) in men and women with bipolar affective disorder (BAD).Patients and methods. We enrolled 100 patients with BAD (F31.3–F31.5 according to ICD-10), including 50 women aged 33.0 [23.0; 50.2] years and 50 men aged 37.5 [29.5; 47.2] years using prospective and retrospective methods. Various antidepressants, normothymics, antipsychotics combinations were used to treat depression. We performed a comparative analysis of treatment efficacy with and without antidepressants in men and women subgroups. Clinical assessment at the baseline and the end of 1, 2, 4, 6-th week of therapy (or at discharge) included a specially developed clinical examination chart and the following psychometric scales: Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression – Severity of illness (CGI-S), Clinical Global Impression – Improvement (CGI-I).Results and discussion. Women tended to have a slower improvement in the condition compared to men. Maximum reduction in MADRS score and a CGI-I, CGI-S higher frequency of clinical improvement and remission was observed in men and women who did not receive antidepressants than patients who did not receive antidepressants. When BAD type was included in the analysis, in patients treated with antidepressants, transient symptoms of the opposite pole occurred in 24.7% of patients of both sexes with bipolar affective I disorder (BAD I) and in 16.8% with bipolar affective II disorder (BAD II). There were no significant gender differences in patients with BAD I, while women predominated in BAD II group (22.5% compared to 7.8% men). No significant treatment-emergent affective switch was observed with tricyclic antidepressants and selective serotonin and norepinephrine reuptake inhibitors in both groups (21; 16.7; 16.7% in men and 28; 21.8; 12.5% in women, respectively). The assessment of intermission revealed that women were significantly more likely to have shorter periods between phases (42% compared to 22% in men). In addition, women were significantly more likely to have shorter periods between phases (42% compared to 22% in men) when the intermission duration was included in the analysis. In some patients with severe depression and infective first-line therapy (anticonvulsants and atypical antipsychotics), antidepressants prescription can increase treatment effectiveness. However, several factors should be considered, such as BAD type and variant, depression severity, treatment-emergent affective switch in history, and gender.Conclusion. A decision about antidepressants' dosage and treatment duration requires a dynamic follow-up of the patient in order to discontinue the antidepressants as fast as possible and decrease the risk of treatment-emergent affective switch and shortening of remission period.

Sex differences in noradrenergic modulation of attention and impulsivity in rats.

Noradrenaline (NE) is closely related to attentive performance and impulsive control. However, the potential sex differences regarding attention and impulsivity under the noradrenergic modulation have been largely neglected. Therefore, our study aimed to investigate whether male and female rats exhibit differential responses to NE-related drugs during the five-choice serial reaction time task (5CSRT). Male and female rats were trained in 5CSRT and administered with different NE drugs after obtaining stable baseline performance: atipamezole, a highly selective α2 receptor antagonist; prazosin, an α1 receptor antagonist; and atomoxetine, a selective NE reuptake inhibitor. Later, prazosin was selected to co-administration with atomoxetine. Male and female rats exhibited equal learning speed, and no significant baseline differences were found as measured by the 5CSRT. Atomoxetine decreased premature responses in both sexes, but the extent of this reduction was different, with the reduction greater in males. Besides, atomoxetine (1.8 mg/kg) increased the error of omissions in females. The high dose of prazosin (0.5 mg/kg) decreased the accuracy only in male rats, but this was ameliorated by the co-administration with atomoxetine. Atomoxetine showed significant improvement in impulsivity, but atomoxetine had less beneficial effects on impulsive control in females than in males, and it even impaired attentional performance in female rats. The α1 receptors were mainly responsible for NE drug-related sex differences in attention rather than impulsivity. The results obtained in this study indicate that the sex differences exist in both attention and impulsivity by the modulation of noradrenaline and raise the concern to improve sex-specific treatments.

Duloxetine (DL) in treatment of oxaliplatin-induced peripheral neuropathy (PN).

195 Background: Oxaliplatin is commonly used to treat many GI cancers, especially colorectal (CRC), pancreatic (PC), and gastric (GC); however, peripheral neuropathy (PN) is the dose-limiting toxicity. Duloxetine (DL) is a second-generation selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of depression, anxiety, PN-associated with diabetes or ongoing pain due to medical conditions such as fibromyalgia. In this retrospective study, we evaluated the role of DL in reduction of oxaliplatin-induced neuropathy. Methods: Patients with GI cancers receiving oxaliplatin-based chemotherapy regimens from Nov 2016 to Nov 2019 were included. Patients with pre-existing PN from other etiologies such as diabetes, alcoholism, autoimmune disease, infections, hereditary, etc. were excluded. Neurological evaluations were performed serially before initiating DL and every 4 weeks thereafter according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. DL was given at 30 mg by mouth (PO) once daily and if tolerated after 3 days, was escalated to 60 mg once daily. Response was calculated to include number of patients with stable PN, improved PN, or no benefit. Adverse toxicities were graded. Results: 53 patients with median age of 53 years (range: 38 – 72) received DL for oxaliplatin-induced PN during treatment of GI cancers (CRC: 40%, PC:30%, GC: 10%, others: 10%). Improvement in PN from higher to lower grades was witnessed at 2 weeks in only 4 patients. At 4 week of DL, 3/53 (6%) patients improved from G3 PN to G2, 6/53 (11%) from G3 to G1, and 28/53 (52.8%) from G2 to G1, 14/53 (26%) and 2/53 (4%) had stable G3 and G2 PN respectively. At 8 week of DL, 10/53 (19%) of patients improved from G3 to G2, 3/53 (6%) from G2 to G1, 23/53 (43%) from G1 to G0, while 11/53 (21%), 2/53 (4%) and 4/53 (8%) remained stable at G1, G2 and G3 respectively. Overall DL resulted in a response rate of 89% and stable PN in 11%. 5 patients had to stop DL due to G3 drowsiness, insomnia, dry mouth and headache. Overall, DL was well-tolerated with majority of toxicities in G1-2 grade: dizziness (15%), drowsiness (11%), sexual side effects (11%), dry mouth (11%), insomnia (8%), headache (8%). In addition to PN, DL helped in improving depression in 50% of these patients and decreased the pain score in an additional 23%. Conclusions: DL resulted in a clinically significant improvement in PN-induced by oxaliplatin with manageable toxicity profile. Additionally, DL also improved depression and pain score. DL may be considered as an option in ameliorating PN in these patients, however, caution must be taken about DL and other drugs interaction. Our study warrants a prospective randomized trial to study the effectiveness of DL in treating oxaliplatin-induced PN. Moreover, cost effectiveness of DL in concurrently improving PN, depression and pain needs to be studied as well.

The progress and development of antidepressants

Major depressive disorder is a common emotional mood disorder disease, which mainly manifests as depression, cognitive impairment, weakened volition activities, loss of appetite, and sleep disorders. Depression is a common mental disorder affecting more than 264 million people worldwide. There are many antidepressant drugs in clinic, e.g., tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin (5-HT) reuptake inhibitors and selective norepinephrine (NA) reuptake inhibitors. Although great progress has been made in the research of new antidepressant drugs, the current clinical use of drugs still has many shortcomings, e.g., the unmet efficiency, slow onset of action, and multiple adverse reactions, which are difficult to meet the requirements of the increasing number of the depressed patients. This article mainly focuses on the development process of antidepressant drugs and compares their effects. Specifically, the N-methyl-D-aspartate receptor as a new antidepressant has a good effect, which is worthy of further study. These results shed light for providing a research idea for the study of new antidepressants.

Aspectos clínicos e principais formas de tratamento para Fibromialgia - Revisão de Literatura

A fibromialgia é considerada uma patologia incurável e uma síndrome idiopática por não ter sua fisiopatologia definida. O portador apresenta sintomas como dor crônica e generalizada, cansaço e dificuldade no sono. É considerada frequente e seu diagnóstico é realizado através da exclusão de outras patologias. Embora ainda não existe um tratamento efetivo, a terapia farmacológica auxilia os portadores a diminuírem os sintomas. O objetivo dessa revisão foi analisar a fisiopatologia envolvida no desenvolvimento da fibromialgia, bem como as terapias farmacológicas, plantas e compostos medicinais atualmente existentes e estudados para o tratamento desta patologia, considerando um período entre 2009 e 2020. Para tanto, os bancos de dados Scielo, Pubmed e Google Acadêmico foram consultados. Desse modo, pode-se constatar que as terapias farmacológicas existentes abrangem principalmente quatro classes de medicamentos que são as drogas antiepiléticas, antidepressivos tricíclicos, inibidores seletivos da recaptação de serotonina (ISRS) e inibidores da recaptação de serotonina noradrenalina, além de relaxantes musculares, benzodiazepínicos, antiinflamatórios analgésicos e fármacos fitoterápicos. Apesar das diversas diretrizes publicadas a respeito do tratamento da fibromialgia, até o momento inexiste terapia plenamente efetiva e diante disso evidencia-se a necessidade de novos fármacos específicos para essa patologia.

Selective serotonin reuptake inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) During Pregnancy and the Risk for Autism spectrum disorder (ASD) and Attention deficit hyperactivity disorder (ADHD) in the Offspring: a True Effect or a Bias? A Systematic Review & Meta-Analysis

BACKGROUND AND OBJECTIVE An inconsistent association between exposure to SSRIs and SNRIs and the risk for ASD and ADHD in the Offspring was observed in observational studies. Some suggest that the reported association might be due to unmeasured confounding. We aimed to study this association and to look for sources of bias by performing a systematic review and meta-analysis. METHODS Medline, Embase, and the Cochrane Library were searched up to June 2019 for studies reporting on ASD and ADHD in the Offspring following exposure during pregnancy. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random- effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for each outcome using the adjusted point estimate of each study. RESULTS Eighteen studies were included in the meta-analysis. We found an association between SSRIs/ SNRIs prenatal use and the risk for ASD and ADHD (OR=1.42, 95% CI: 1.23-1.65, I2=58%; OR=1.26, 95% CI: 1.07-1.49, I2=48%, respectively). Similar findings were obtained in women who were exposed to SSRIs/SNRIs before pregnancy, representing statistically significant association with ASD (OR=1.39, 95% CI: 1.24-1.56, I2=33%) and ADHD (OR=1.63, 95% CI: 1.50-1.78, I2=0%) in the Offspring, although they were not exposed to those medications in utero. CONCLUSIONS Although we found an association between exposure to SSRIs/SNRIs during pregnancy and the risk for ASD and ADHD, an association with those disorders was also present for exposure pre-pregnancy, suggesting that the association might be due to unmeasured confounding. We are aiming to further assess the role of potential unmeasured confounding in the estimation of the association and perform a network meta-analysis.

127-OR: Pharmacologic Management of Diabetic Peripheral Neuropathy

Approximately half of all people with diabetes develop diabetic peripheral neuropathy (DPN) and half experience pain. Guidelines recommend pregabalin, gabapentin, and duloxetine (a selective norepinephrine and serotonin reuptake inhibitor [SNRI]) due to their demonstrated efficacy and safety. Topical analgesics, tricyclic anti-depressants (TCA), and anti-convulsants may also be used. Opioids are discouraged due to lack of effectiveness, risk of addiction, and safety concerns. To promote safe evidence-based pain management, we examined pain medication use by adults diagnosed with DPN between 2002-2019 in an integrated healthcare system across 5 states. We identified 13,815 adults with newly diagnosed DPN; mean age 66 (SD, 13) years, 42% female, 93% white, 29% insulin-treated. Overall, 56% received a pain medication from DPN diagnosis (1 month prior or continued from baseline) to 2 years later. Limiting to treatment pathways observed in ≥1% of cases, opioids were the most used 1st line medication, followed by gabapentin and others (Figure). Opioids and gabapentin were also the most prevalent 2nd line drugs. High rates of opioid use by patients with DPN, a life-long pain syndrome, are concerning particularly as safer effective treatment options are available. Further research is needed to identify drivers of opioid use and barriers to evidence-based alternatives, and develop interventions to improve DPN management in clinical practice. Disclosure J. Fan: None. M.M. Jeffery: None. W. Hooten: None. N. Shah: None. R.G. McCoy: None. Funding National Institutes of Health (K23DK114497)

Solriamfetol in excessive daytime sleepiness: a profile of its use

Oral solriamfetol (Sunosi™), a selective dopamine and norepinephrine reuptake inhibitor, is approved to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnoea (OSA) in the USA and EU. In phase 3 trials in patients with narcolepsy or OSA, relative to placebo, solriamfetol within the recommended dosage for narcolepsy (75–150 mg/day) or OSA (37.5–150 mg/day) improved wakefulness and reduced sleepiness, together with patient- and clinician-rated global improvements. The clinical benefits of solriamfetol were maintained with longer-term treatment. Solriamfetol is generally well tolerated, with most adverse events being of mild to moderate severity.

Healthcare resource use and cost associated with timing of pharmacological treatment for major depressive disorder in the United States: a real-world study

Background: Guidelines recommend selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) as first-line treatments for major depressive disorder (MDD) and emphasize the importance of early pharmacological treatment as key factors to treatment success.Objectives: To compare the MDD-related healthcare resource utilization (HCRU) and cost among patients (1) with early vs late pharmacological treatment initiation and (2) achieving minimum therapeutic dose (MTD) early vs late.Methods: The MarketScan database (2010–2015) was used. Adults who were newly-treated with SSRI/SNRI within 12 months after the initial MDD diagnosis (index) were included. Patients who initiated SSRI/SNRI within 2 weeks of the index date were defined as early initiators; those who reached MTD within 4 weeks of index date were defined as early MTD achievers. MDD-related HCRU and costs per year after the index date were compared between early and late initiators and between early and late achievers using propensity score matching and generalized linear models.Results: Of the 55,539 patients, 60% were early initiators and 61% were early MTD achievers. The mean number of MDD-related outpatient visits per year were significantly higher for late initiator (6.7 vs 4.2, p < .001) and late MTD achievers (6.5 vs 4.5, p < .001) vs their early counterparts. Mean annual MDD-related outpatient, drug, and total cost were significantly higher for late initiators and MTD achievers vs the early groups.Conclusions: There is an opportunity to improve outcomes by treating MDD patients with SSRI/SNRI within 2 weeks and at or above the MTD within 4 weeks of diagnosis or less.

Solriamfetol for the treatment of excessive daytime sleepiness associated with narcolepsy

ABSTRACTIntroduction: Narcolepsy is a chronic disabling condition, excessive daytime somnolence is the main symptoms of it. There is currently no cure for narcolepsy, and hence there is a great need for new treatment options. Solriamfetol is a new selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects. The purpose of this paper is to review solriamfetol.Areas covered: The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, and safety of solriamfetol are introduced in this paper.Expert opinion: Solriamfetol can bind to dopamine and norepinephrine transporters and inhibit reuptake of dopamine and norepinephrine. Clinical trials showed that solriamfetol could significantly improve the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy. Solriamfetol was well tolerated. Very common adverse reactions were headache, nausea, decreased appetite, insomnia, and anxiety.

Validated Microemulsion Liquid Chromatography-Fluorescence Method for the Quantification of Duloxetine and its Two Main Metabolites in Plasma: Application to Clinical Pharmacokinetic Studies

Background: Duloxetine (DL) is a selective serotonin and norepinephrine reuptake inhibitor. The drug is used in the treatment of major depression, anxiety, pain related to diabetic peripheral neuropathy and stress urinary incontinence. &lt;/P&gt;&lt;P&gt; Objective: This study described, for the first time, the development and validation of a highly selective and sensitive microemulsion liquid chromatography-fluorescence (MELC-FL) method with low environmental pollution and without extraction steps for the simultaneous quantification of DL, and its two main metabolites; 5-hydroxy-6-methoxy duloxetine (5-HDL) and 4-hydroxy duloxetine glucuronide (4- HDLG) in plasma. Methods: The studied analytes and methyl paraben (an internal standard) were detected using excitation and emission wavelengths of 280 and 340 nm, respectively. The analysis was performed on Water Symmetry C18 analytical column (100 Å, 150 mm x 3.9 mm, 5 µm) by directly injecting the plasma after appropriate dilution with microemulsion mobile phase. Total analytical run time was 4 min. Results: The MELC-FL method was statistically validated according to the FDA guidelines for bioanalytical methods for linearity, accuracy, precision, specificity, robustness, and stability. Linear calibration plots were achieved in the ranges of 25-1200 ng/mL for DL and 50-1500 ng/mL for 5-HDL and 4- HDLG (r2 ≥ 0.997) in rat plasma. The intra- and inter- assay precisions and accuracy were acceptable. The overall recoveries of DL and its two main metabolites from rat plasma were between 97.12% and 103.12% with an RSD value between 0.34% and 4.57%. Conclusion: The present study supports the possible use of the microemulsion mobile phase in LC as a “greener ” mobile phase. The developed method offered an advantage in the form of direct analysis of biological samples after appropriate dilution with eco-friendly microemulsion mobile phase, which decreased the possibility of sample loss during analysis. The developed assay was successfully applied in a pharmacokinetic study and it established the applicability of the method for the determination of concentration-time profiles of DL and its two main metabolites in rat plasma after systemic administration.

Abstract TMP44: Gender and Race/ethnic Disparities in Psychotropic Medication Prescription at Discharge Among TIA and Mild/moderate Stroke Patients in the Discharge Educational Strategies for Reduction of Vascular Events (DESERVE) Study

Depression and anxiety are common after stroke. Little is known about the factors associated with prescription of antidepressants (AD) and anti-anxiety (AA) medications post-stroke. The study used data from DESERVE, a randomized educational trial to reduce vascular risk in a multi-ethnic cohort of TIA and mild/moderate stroke patients in New York City. The study outcome was any AD or AA prescription at discharge, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants, norepinephrine-dopamine reuptake inhibitors, serotonin antagonist and reuptake inhibitors, anxiolytics, and benzodiazepines. Chi-square, Fisher’s exact, and Wilcoxon rank sum tests were used to examine the association between patient characteristics and AD/AA prescription. Factors associated with the outcome at p&lt;0.10 in bivariate analysis were examined using multiple logistic regression. Of the 236 patients with medication information, 21.2% were prescribed an AD or AA, most commonly SSRIs/SNRIs (82.0%) and benzodiazepines (31.4%). In the adjusted model, males (OR=0.37 95% CI: 0.16, 0.84) and Non-Hispanic black/other race patients (OR=0.08, 95% CI: 0.03, 0.24) had significantly lower odds of AD/AA prescription. Probable depression pre-discharge (Center for Epidemiologic Studies-Depression scale ≥ 16) (OR=4.11, 95% CI: 1.46, 11.55) and prior psychiatry history (OR=2.82, 95% CI: 1.02-7.83) were associated with greater odds of AD/AA prescription. Non-significant differences in AD/AA prescription were noted on the basis of stroke severity, modified Rankin scale, and Hispanic ethnicity (Table 1). Prescription of ADs/AAs at stroke discharge was common and associated with gender and race/ethnicity independent of other factors. Further research is needed to better understand disparities in post-stroke psychotropic medication prescription.

Clinical implications of selective serotonin reuptake inhibitors-selective serotonin norepinephrine reuptake inhibitors pharmacogenetics during pregnancy and lactation.

Depression occurs during pregnancy in 3.9-12.8% of the women. The different serotonin reuptake inhibitors (SRIs) are metabolized in the liver by CYP450 enzymes. CYP2D6 metabolizes paroxetine, fluoxetine, duloxetine and venlafaxine, while CYP2C19 deactivates citalopram and escitalopram. Polymorphisms in these enzymes change the metabolic clearance and levels of these drugs. Higher metabolism of most SRIs in late pregnancy results in lower maternal levels, which could result in decreased efficacy. Very few studies have addressed the potential interaction between pregnancy-induced increase in 2D6 metabolism and specific genotypes of the women, suggesting that ultra-rapid and extensive metabolizers exhibit lower serum concentrations than the other slower genotypes. Preliminary studies suggest that some genotypes of the serotonin transporter (SLC6A4) promoter are associated and are linked to adverse effects in infants with SRI exposure during pregnancy. Presently, there are no clear clinical implications of SRI pharmacogenetic status in pregnancy and lactation. In late pregnancy, women may exhibit lower steady state concentrations of these drugs, necessitating increased doses but these are presently guided clinically and not through genotyping. Much more work is needed to define whether SRI genotype has clinical implications and predictive value for either mother or offspring.

Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short-term histological outcomes after hypoxic-ischemic brain injury in the neonatal male rat

BackgroundDespite the recent progress of perinatal medicine, perinatal hypoxic-ischemic (HI) insult remains an important cause of brain injury in neonates, and is pathologically characterized by neuronal loss and the presence of microglia. Neurotransmitters, such as norepinephrine (NE) and glutamate, are involved in the pathogenesis of hypoxic-ischemic encephalopathy via the interaction between neurons and microglia. Although it is well known that the monoamine neurotransmitter NE acts as an anti-inflammatory agent in the brain under pathological conditions, its effects on perinatal HI insult remains elusive. Atomoxetine, a selective NE reuptake inhibitor, has been used clinically for the treatment of attention-deficit hyperactivity disorder in children. Here, we investigated whether the enhancement of endogenous NE by administration of atomoxetine could protect neonates against HI insult by using the neonatal male rat model. We also examined the involvement of microglia in this process. MethodsUnilateral HI brain injury was induced by the combination of left carotid artery dissection followed by ligation and hypoxia (8% O2, 2 h) in postnatal day 7 (P7) male rat pups. The pups were randomized into three groups: the atomoxetine treatment immediately after HI insult, the atomoxetine treatment at 3 h after HI insult, or the vehicle treatment group. The pups were euthanized on P8 and P14, and the brain regions including the cortex, striatum, hippocampus, and thalamus were evaluated by immunohistochemistry. ResultsHI insult resulted in severe brain damage in the ipsilateral hemisphere at P14. Atomoxetine treatment immediately after HI insult significantly increased NE levels in the ipsilateral hemisphere at 1 h after HI insult and reduced the neuronal damage via the increased phosphorylation of cAMP response element-binding protein (pCREB) in all brain regions examined. In addition, the number of microglia was maintained under atomoxetine treatment compared with that of the vehicle treatment group. To determine the involvement of microglia in the process of neuronal loss by HI insult, we further examined the influence of hypoxia on rat primary cultured microglia by the quantitative real-time polymerase chain reaction. Hypoxia did not cause the upregulation of interleukin-1beta (IL-1β) mRNA expression, but decreased the microglial intrinsic nitric oxide synthase (iNOS)/arginase1 mRNA expression ratio. NE treatment further decreased the microglial iNOS/arginase1 mRNA expression ratio. In contrast, no significant neuroprotective effect was observed at P14 when atomoxetine was administered at 3 h after HI insult. ConclusionsThese findings suggested that the enhancement of intrinsic neurotransmitter NE signaling by a selective NE reuptake inhibitor, atomoxetine, reduced the perinatal HI insult brain injury. In addition, atomoxetine treatment was associated with changes of TUNEL, pCREB, and BDNF expression levels, and microglial numbers, morphology, and responses.

Clinical Management of Anxiety Disorders

Anxiety disorders are characterized by excessive fear and anxiety accompanied by associated behavioral disturbances that cause significant impairment in social and occupational functioning. Anxiety is a complex mood state that involves physiologic, cognitive, and behavioral components. This review describes the five anxiety disorders most commonly diagnosed in adults: social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, and specific phobia. Diagnostic criteria for these disorders are presented along with empirically supported psychological and pharmacologic treatment approaches. Decades of evidence have indicated that for anxiety disorders of mild to moderate severity, cognitive-behavioral therapy (CBT) should be first-line treatment. CBT interventions for anxiety, including psychoeducation, cognitive restructuring, exposure, applied relaxation/breathing retraining, and skills training, are presented with descriptions of how they may be adapted to particular diagnoses, along with data for their efficacy. Data suggest that selective serotonin and norepinephrine reuptake inhibitors are pharmacologic treatments of choice for anxiety and may be used in combination with CBT for moderate to severe symptoms. d-Cycloserine is an emerging treatment that may enhance outcomes in anxiety disorders by optimizing exposure therapy through the facilitation of fear extinction. This review contains 7 figures, 12 tables, and 105 references. Key words: agoraphobia, anxiety, generalized anxiety disorder, panic disorder, phobias, social anxiety disorder

Clinical Management of Anxiety Disorders

Anxiety disorders are characterized by excessive fear and anxiety accompanied by associated behavioral disturbances that cause significant impairment in social and occupational functioning. Anxiety is a complex mood state that involves physiologic, cognitive, and behavioral components. This review describes the five anxiety disorders most commonly diagnosed in adults: social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, and specific phobia. Diagnostic criteria for these disorders are presented along with empirically supported psychological and pharmacologic treatment approaches. Decades of evidence have indicated that for anxiety disorders of mild to moderate severity, cognitive-behavioral therapy (CBT) should be first-line treatment. CBT interventions for anxiety, including psychoeducation, cognitive restructuring, exposure, applied relaxation/breathing retraining, and skills training, are presented with descriptions of how they may be adapted to particular diagnoses, along with data for their efficacy. Data suggest that selective serotonin and norepinephrine reuptake inhibitors are pharmacologic treatments of choice for anxiety and may be used in combination with CBT for moderate to severe symptoms. d-Cycloserine is an emerging treatment that may enhance outcomes in anxiety disorders by optimizing exposure therapy through the facilitation of fear extinction. This review contains 7 figures, 12 tables, and 105 references. Key words: agoraphobia, anxiety, generalized anxiety disorder, panic disorder, phobias, social anxiety disorder