SNRI Venlafaxine Research Articles

Posttraumatski stresni poremećaj - pregled novina u dijagnostičkim i terapijskim pristupima

Posttraumatic stress disorder (PTSD) is a complex condition, a common and disabling psychiatric disorder that causes immense suffering for millions of people. It is associated with a high rate of functional impairment, somatic complaints, a risk of suicide and comorbid psychiatric disorders, as well as extraordinary costs for health care system. The diagnosis of PTSD requires evidence of exposure to trauma, and is characterized by symptoms of re-experiencing, avoidance, and changes in arousal and reactivity. The American classification system added another cluster of symptoms related to negative changes in cognition and mood related to trauma, while the European classification system added complex PTSD as a new diagnosis. No evidence supported any particular intervention as a universal prevention strategy. CBT-TF, CBT and EMDR treatment had positive effects. Psychotherapy is the first line of choice in the treatment of PTSD. Trauma-focus interventions are recommended: CBT-TF, PE and EMDR, as well as stress management therapy. Pharmacotherapy approaches should start with one of the first-line options that include an SSRI such as fluoxetine, paroxetine, or sertraline, or the SNRI venlafaxine. Research evaluating combined psychological and pharmacological treatments for PTSD is limited and requires further study, but certain forms of PTSD require an integrative and multidisciplinary approach. Prevention, early detection, and clear treatment guidelines could be the best choice for every traumatized person as well as for the health care system.

BDNF exon IV promoter methylation and antidepressant action: a complex interplay

BackgroundBDNF exon IV promoter methylation is a potential biomarker for treatment response to antidepressants in MDD. We have previously shown CpG-87 methylation as a successful biomarker for the prediction of non-response to monoaminergic antidepressants like the SSRI Fluoxetine or the SNRI Venlafaxine. This study aimed to dissect the biological evidence and mechanisms for the functionality of CpG-87 methylation in a cell culture model.ResultsWe observed a significant interaction between methylation and antidepressant-mediated transcriptional activity in BDNF exon IV promoter. In addition, antidepressant treatment increased the promoter methylation in a concentration-dependent manner. Further single CpG methylation of -87 did not change the promoter activity, but methylation of CREB domain CpG-39 increased the transcriptional activity in an antidepressant-dependent manner. Interestingly, DNMT3a overexpression also increases the BDNF exon IV transcription and more so in Venlafaxine-treated cells.ConclusionsThe study strengthens the previously reported association between antidepressant treatment and BDNF exon IV promoter methylation as well as hints toward the mechanism of action. We argue that potential CpG methylation biomarkers display a complex synergy with the molecular changes at the neighboring CpG positions, thus highlighting the importance of epiallele analyses.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders – Version 3. Part II: OCD and PTSD

Aim This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive–Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008. Method A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments. Result The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD (n = 291) and PTSD (n = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders. For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs. Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated. For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option. Conclusion OCD and PTSD can be effectively treated with CBT and medications.

Multinational Investigation of Fracture Risk with Antidepressant Use by Class, Drug, and Indication.

OBJECTIVESAntidepressants increase the risk of falls and fracture in older adults. However, risk estimates vary considerably even in comparable populations, limiting the usefulness of current evidence for clinical decision making. Our aim was to apply a common protocol to cohorts of older antidepressant users in multiple jurisdictions to estimate fracture risk associated with different antidepressant classes, drugs, doses, and potential treatment indications.DESIGNRetrospective (2009–2014) cohort study.SETTINGFive jurisdictions in the United States, Canada, United Kingdom, and Taiwan.PARTICIPANTSOlder antidepressant users—subjects were followed from first antidepressant prescription or dispensation to first fracture or until the end of follow‐up.MEASUREMENTSThe risk of fractures with antidepressants was estimated by multivariable Cox proportional hazards models using time‐varying measures of antidepressant dose and use vs nonuse, adjusting for patient characteristics.RESULTSBetween 42.9% and 55.6% of study cohorts were 75 years and older, and 29.3% to 45.4% were men. Selective serotonin reuptake inhibitors (SSRIs) (48.4%‐60.0%) were the predominant class used in North America compared with tricyclic antidepressants (TCAs) in the United Kingdom and Taiwan (49.6%‐53.6%). Fracture rates varied from 37.67 to 107.18 per 1,000. The SSRIs citalopram (hazard ratio [HR] = 1.23; 95% confidence interval [CI] = 1.11‐1.36 to HR = 1.43; 95% CI = 1.11‐1.84) and sertraline (HR = 1.36; 95% CI = 1.10‐1.68), the SNRI duloxetine (HR = 1.41; 95% CI = 1.06‐1.88), TCAs doxepin (HR = 1.36; 95% CI = 1.00‐1.86) and imipramine (HR = 1.16; 95% CI = 1.05‐1.28), and atypicals (HR = 1.34; 95% CI = 1.14‐1.58) increased fracture risk in some but not all jurisdictions. In the United States and the United Kingdom, fracture risk with all classes was higher when prescribed for depression than chronic pain, a trend that is likely explained by drug choice.CONCLUSIONThe fracture risk for patients may be reduced by selecting paroxetine, an SSRI with lower risk than citalopram, the SNRI venlafaxine over duloxetine, and the TCA amitriptyline over imipramine or doxepin. There is uncertainty about the risk associated with the atypical antidepressants. J Am Geriatr Soc 68:1494‐1503, 2020.

Recent guidelines for evidence-based pharmacological treatment of social anxiety disorder

Pharmacological and psychological treatmentsThe findings of meta-analyses and randomized placebo-controlled treatment studies indicate that a range of approaches are efficacious in acute treatment. Pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment. However, acute treatment with cognitive therapy (group or individual) may be associated with a reduced risk of symptomatic relapse at follow-up. Cognitive behaviour therapy is efficacious in adults and children: cognitive therapy appears superior to exposure therapy, but the evidence for the efficacy of social skills training is less strong. It is unlikely that the combination of pharmacological with psychological treatments is associated with greater overall efficacy than with either treatment, when given alone, as only 1 of 4 studies of the relative efficacy of combination treatment found evidence for superior efficacy.Efficacy and length of acute pharmacological treatmentAntidepressant drugs with proven efficacy include most SSRIs, the SNRI venlafaxine, the MAOI phenelzine and the RIMA moclobemide: the potential efficacy of tricyclic antidepressants is unknown. Some benzodiazepines and anticonvulsants and the antipsychotic olanzapine also appear efficacious in acute treatment. A number of small single-dose placebo-controlled crossover studies together suggest that beta-blockers can be beneficial in reducing anxiety symptoms in individuals with ‘performance anxiety’ (for example, when speaking in public), which overlaps with mild non-generalized social anxiety disorder. Acute treatment studies indicate that the proportion of responding patients increases steadily over time. A post-hoc analysis of the clinical trial database with paroxetine indicates that many non-responders to treatment at 8 weeks become responders with a further 4 weeks of double-blind treatment: however a post-hoc analysis of the clinical trial database for escitalopram indicates that response is unlikely if there is no onset of clinical effect within the first 4 weeks of treatment.Longer-term treatment and further treatment after non-responseThe findings of randomized placebo-controlled relapse prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (clonazepam, escitalopram, paroxetine, pregabalin, sertraline) for up to six months. Fixed-dose randomized controlled trials do not provide consistent evidence of a dose-response relationship with antidepressant drugs: but a fixed-dose study of pregabalin found that only the higher daily dosage was efficacious. A double-blind randomized controlled dosage escalation trial found no advantage for increasing to a higher daily dosage (of duloxetine), when compared to continuing treatment with a lower dosage. Switching between treatments with proven efficacy may be helpful. An uncontrolled study of augmentation of SSRI treatment with buspirone found some evidence of beneficial effects; but a placebo-controlled crossover-study of the augmentation of paroxetine with pindolol found no evidence of efficacy. A small placebo-controlled study of the augmentation of paroxetine with clonazepam found the combination was marginally short of superiority, when compared to paroxetine alone.Disclosure of interestThe author has not supplied his declaration of competing interest.

Drug-, dose- and sex-dependent effects of chronic fluoxetine, reboxetine and venlafaxine on open-field behavior and spatial memory in rats

In an effort to address the need to include both sexes in studies of effects of the SSRI fluoxetine, the NRI reboxetine and the SNRI venlafaxine on anxiety-related behavior and memory along with the use of chronic drug administration, male and female PVG/c rats were fed diets containing two doses of each drug for 21 days. The rats’ anxiety level was then assessed in an open field. Short-term spatial memory for a brightness change in a Y maze was also measured. While there was little evidence of anxiolytic effects of any of the drugs, both fluoxetine and, to a lesser extent, venlafaxine appeared to be mainly anxiogenic in their action depending on both dose and sex. Reboxetine was relatively ineffective in this respect. Ability to locate the Y-maze arm that had changed (from white to black) seemed to be impaired for male (but not female) rats by both fluoxetine and venlafaxine and, to a much lesser extent, by reboxetine. Given the relative ineffectiveness of reboxetine in either test, it is possible that the effects of the other two drugs on both anxiety and memory were mainly due to their serotonin reuptake inhibiting properties. The differences that occurred between males and females in responsiveness to all three drugs supported the long-held view that both sexes should be investigated in studies of this sort, especially in view of reports of sex differences in effects of clinically prescribed antidepressants.

Treatment and outcome in medication overuse headache patients

Results One hundred forty six patients (29 males and 117 females) with MOH were evaluated (mean age 38.5 ±12.7 years; mean body mass index 26.1±4.44). Patients overused triptans (38.9%), analgesics (61.1%), NDAIDs (48.4%), codein plus paracetamol (77.6%), bezodiazepines (2.3%), or ergotamine (17.5%). Scores for Hamilton scale for anxiety and depression were 23.9±5.6 and 18.8±6.5, respectively. Prophylactic treatment consisted of naproxen 1000mg (plus gastroproplylaxis), SNRI (venlafaxine 150-300mg/d, or mirtazapine 45-90mg/d) and one of three agents: propranolol (160-320mg/d), topiramate (100mg) or valproate (500-1500mg/d). In cases of anxiety disorder comorbidity (HAM-A score>18) prazepam was added (10-20mg/d). All patients were advised to withdraw immediately the substance overused. After one to three months treatment 37% and 45.6% of patients reported a greater of 50% or 75% decrease of days with headache per month, respectively. The 17.3% of the patient population did not respond to treatment. Conclusion Immediate withdraw of substance overused combined with a strong prophylactic treatment, which included naproxen, SNRIs and preventative antimigraine agents is efficient to decrease headache impact in most patients with MOH.

124. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on microglia

Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the frontline pharmacological treatment options for major depression. While these drugs have long been assumed to exert their antidepressant effects because of their ability to alter central monoamine levels, they have also been shown to exert anti-inflammatory effects. Recently it has become apparent that these drugs can also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. From a pharmacological standpoint, much critical information remains unknown. In particular, the relative efficacy of these drugs in modulating microglial responses is yet to be determined. To address these issues, we evaluated the ability of different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production after stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-alpha and NO production. We then investigated whether these effects might involve either beta-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling may be partially involved in regulating the anti-inflammatory response. Findings such as these could suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.

The effects of most commonly prescribed second generation antidepressants on driving ability: a systematic review

Driving a car is vital for the functional autonomy of patients to take part in activities of daily living. Both psychopathologic symptoms and psychopharmacologic treatment may impair driving ability. This article provides a systematic review of published studies (1980-2011) on commonly prescribed newer antidepressants and driving performance. A total of 21 studies could be included in the review, indicating that there is a lack of controlled patient studies. Investigations on newer antidepressants were frequently undertaken in healthy subjects focusing on acute or subchronic effects of application, predominately in young male participants, with dosages usually given in an ambulatory setting. No data, according to selection criteria, were found with respect to agomelatine, duloxetine, bupropion and viloxazine. There is evidence that the SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, paroxetine) and the SNRI venlafaxine have no deleterious effects on driving ability. Acute use of mirtazapine does produce impairments that diminish to some degree when given as a nocturnal dose and cannot be seen after repeated dosing in healthy controls. Patients obviously benefit from treatment with newer antidepressants; however, at least a subgroup does not reach performance level of healthy subjects. More patient studies are needed that elaborate specific relationships between clinical subtypes of the illness and response to different antidepressants, considering course and duration of illness, co-morbidities and not least neuropsychological and neurobiological characteristics.

Fingolimod (Gilenya(R)) in Combination with an SSRI or SNRI Antidepressant in Multiple Sclerosis Patients with Mild to Moderate Depression: Design of a Phase IIIb Study (REGAIN) (P01.135)

Objective: The primary endpoint is the safety and tolerability profile of the combination of an SSRI or SNRI antidepressant with fingolimod in MS patients (expanded disability status scale (EDSS) 0–6.5) who are suffering mild to moderate depression (BDI-II 14-28). In addition, the efficacy of the combination therapy on quality of life, treatment satisfaction and other MS related sequelae will be exploratively assessed. Furthermore, in terms of health economics, the MS-specific and depression-specific use of resources will be evaluated. Background Almost half of all patients with multiple sclerosis (MS) are affected by concomitant psychological diseases, depression being most frequent (46%). The 12-month prevalence of depression in MS patients is 26%, which is three times higher than in the general population. Although some studies have shown a positive effect of selective serotonin/noradrenaline or serotonin re-uptake inhibitors (SNRIs or SSRIs, respectively), there is currently no established drug treatment of depression in MS patients. Therefore, in this open-label study, the safety and tolerability of the combination of fingolimod and an SSRI or SNRI antidepressant will be investigated in MS patients with mild to moderate depression. Design/Methods: In the REGAIN study ( R educe d E pression with G ilenya A nd SNRI/SSRI ant I depressant in MS-patie N ts) 375 patients with relapsing remitting MS and a mild to moderate depression, will be included. Patients will be pre-treated for 2 weeks with fingolimod, followed by a 16-week concomitant antidepressant treatment phase, with either an SSRI or an SNRI (Citalopram, Fluoxetine or Venlafaxine), at the discretion of the investigator, while maintaining on fingolimod therapy. After 8 and 16 weeks, the safety and tolerability of the combination therapy will be assessed. Results: Baseline demographics will be available in April 2012. Conclusions: This study will provide first-time data on the safety and tolerability of a combination therapy of fingolimod and an SSRI or SNRI antidepressant in MS patients with mild to moderate depression. Supported by: Novartis Pharma GmbH; Germany. Disclosure: Dr. Schuh has received personal compensation for activities with Novartis as an employee. Dr. Meergans has received personal compensation for activities with Novartis as an employee. Dr. Bayas has received personal compensation for activities as a investigator.

A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia

Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti-inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated. Accordingly, the current study evaluated the ability of five different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumour necrosis factor-α (TNF-α) and nitric oxide (NO) production after 4 and 24 h stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-α and NO production. We then investigated whether these effects might involve either β-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling is involved in regulating the anti-inflammatory response. These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.

Placental Transfer of SSRI and SNRI Antidepressants and Effects on the Neonate

We investigated placental transfer and neurobehavioural effects in neonates exposed to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline (SSRI's), or to venlafaxine (an SNRI). Women receiving antidepressants during pregnancy and their neonates were studied. Cord and maternal drug concentrations were measured at birth and in the neonates plasma on day 3. Neonates were also assessed using a range of neurobehavioral tests and compared to controls. Median cord/maternal distribution ratio was 0.7-0.86 (range) for SSRIs, 0.72 for the SNRI venlafaxine and 1.08 for the O-desmethyl metabolite. Neonatal abstinence scores were significantly higher (p<0.05) in exposed infants than controls on day 1. Brazelton scores for habituation, social-interactive, motor and autonomic clusters, and serotonin scores were significantly greater (p<0.05) in exposed infants. Transfer of SSRIs and SNRIs across the placenta was substantial. Neonates developed mild behavioral symptoms in the early perinatal period but these were self-limiting and similar for both SSRIs and the SNRI venlafaxine.

Treatment of generalized anxiety disorder

Treatment of generalized anxiety disorder

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Differential modification of d-fenfluramine-induced serotonergic responses by acute and chronic sertraline and fluoxetine administration to rats

In an effort to address the need to include both sexes in studies of effects of the SSRI fluoxetine, the NRI reboxetine and the SNRI venlafaxine on anxiety-related behavior and memory along with the use of chronic drug administration, male and female PVG/c rats were fed diets containing two doses of each drug for 21 days. The rats’ anxiety level was then assessed in an open field. Short-term spatial memory for a brightness change in a Y maze was also measured. While there was little evidence of anxiolytic effects of any of the drugs, both fluoxetine and, to a lesser extent, venlafaxine appeared to be mainly anxiogenic in their action depending on both dose and sex. Reboxetine was relatively ineffective in this respect. Ability to locate the Y-maze arm that had changed (from white to black) seemed to be impaired for male (but not female) rats by both fluoxetine and venlafaxine and, to a much lesser extent, by reboxetine. Given the relative ineffectiveness of reboxetine in either test, it is possible that the effects of the other two drugs on both anxiety and memory were mainly due to their serotonin reuptake inhibiting properties. The differences that occurred between males and females in responsiveness to all three drugs supported the long-held view that both sexes should be investigated in studies of this sort, especially in view of reports of sex differences in effects of clinically prescribed antidepressants.