Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Combinations of 1,8-cineol and oseltamivir for the treatment of influenza virus A (H3N2) infection in mice.

It is need for development of new means against influenza virus due to the lack of efficacy of available therapeutic strategies. In previous research, 1,8-cineol exert its inhibition of nuclear factor (NF)-κB, the main regulator of cytokine and chemokine production in influenza, and anti-inflammatory activity. These fact supports and helps establish the hypothesis that 1,8-cineol may have synergism with an antiviral on influenza virus infection. The combined effect of 1,8-cineol with oseltamivir in a mouse type A influenza virus (Victoria/3/75,H3N2) model were examined. We initially tested combinations of 1,8-cineol (30, 60, and 120 mg/kg/day) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/day). In addition, the 0.4 mg/kg/day of oseltamivir combined with 120 mg/kg of 1,8-cineol was selected for further combination studies. Oseltamivir was 30%, 40%, and 60% protective at 0.1, 0.2, and 0.4 mg/kg/d. Combinations of 1,8-cineol (30, 60, and 120 mg/kg/d) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/d) increased the number of survivors and mean survival time (MST) following combination treatment was greater than monotherapy alone. Three dimensional analysis of drug interactions using the MacSynergy method showed a strong synergistic effect of these drug combinations. Survival, MST, lung parameters (lung index, viral titers, and pathology), and cytokines (IL-10, TNF-α, IL-1ß, and IFN-γ) expression in lung demonstrated the high effectiveness of the combination. Combined treatment was associated with longer MST and more reduced cytokine levels than oseltamivir alone. These data demonstrate that combinations of 1,8-cineol and oseltamivir have synergistic effect against influenza A virus (H3N2) infection.

Efficacy and Tolerability of a Cosmetic Skin Care Product With Trans-4-t-butylcyclohexanol and Licochalcone A in Subjects With Sensitive Skin Prone to Redness and Rosacea.

BACKGROUND: Sensitive skin and rosacea are skin conditions, which may affect the quality of life of the patients considerably. In vitro and in vivo data indicated that the combination of trans-t-butylcyclohexanol and licochalcone A is an effective combination for alleviating the increased sensitivity of rosacea subtype I.

OBJECTIVE: Objective of this open dermocosmetic study was to investigate the efficacy and tolerability of a skin care product containing the anti-inflammatory licochalcone A and the TRPV1 antagonist trans-t-butylcyclohexanol in subjects with sensitive skin prone to redness and rosacea.

METHODS: 1221 subjects with sensitive skin and rosacea stage 0-II applied the test product twice daily for 4 weeks. Clinical assessment of sensitive skin and rosacea symptoms were performed at baseline and after 4 weeks. Additionally, at treatment end the test subjects filled a self-assessment questionnaire.

RESULTS: After 4 weeks of application, both, clinical and subjective assessment have shown improvement of all symptoms of sensitive skin and rosacea in a significant number of subjects (P less than 0.001). The test product was efficacious and very well tolerated also when used in conjunction with pharmacological treatments of the skin condition under scrutiny.

Conclusions: The study confirmed the good tolerability and efficacy of the skin care product in the management of sensitive skin prone to redness and rosacea when used alone or in combination with other therapies.

J Drugs Dermatol. 2017;16(6):605-611.

Development and Sequential Analysis of a New Multi-Agent, Anti-Acne Formulation Based on Plant-Derived Antimicrobial and Anti-Inflammatory Compounds.

The antibacterial and anti-inflammatory potential of natural, plant-derived compounds has been reported in many studies. Emerging evidence indicates that plant-derived essential oils and/or their major compounds may represent a plausible alternative treatment for acne, a prevalent skin disorder in both adolescent and adult populations. Therefore, the purpose of this study was to develop and subsequently analyze the antimicrobial activity of a new multi-agent, synergic formulation based on plant-derived antimicrobial compounds (i.e., eugenol, ß-pinene, eucalyptol, and limonene) and anti-inflammatory agents for potential use in the topical treatment of acne and other skin infections. The optimal antimicrobial combinations selected in this study were eugenol/ß-pinene/salicylic acid and eugenol/ß-pinene/2-phenoxyethanol/potassium sorbate. The possible mechanisms of action revealed by flow cytometry were cellular permeabilization and inhibition of efflux pumps activity induced by concentrations corresponding to sub-minimal inhibitory (sub-MIC) values. The most active antimicrobial combination represented by salycilic acid/eugenol/ß-pinene/2-phenoxyethanol/potassium sorbate was included in a cream base, which demonstrated thermodynamic stability and optimum microbiological characteristics.

Effect of 1.8-Cineole in Dermatophagoides pteronyssinus-Stimulated Bronchial Epithelial Cells and Mouse Model of Asthma.

1.8-Cineole (eucalyptol) is a phytoncide, a volatile organic compound derived from plants. Phytoncides are known to have an anti-inflammatory effect. However, the effects of 1.8-cineole in house dust mite (HDM)-stimulated bronchial epithelial cells are poorly understood. The objective of this study was to assess the effect of 1.8-cineole in HDM-stimulated bronchial epithelial cells and in the HDM-induced murine asthma model. The purpose of the present study is to evaluate the anti-inflammatory effects and mechanism of 1.8-cineole action in HDM-induced airway inflammation. Human bronchial epithelial cells (HBECs) were cultured with Dermatophagoides pteronyssinus (Der p) and 1.8-cineole. Cytokine protein levels, phosphorylation of protein kinases, and intracellular Toll-like receptor 4 (TLR4) expressions were measured. In the murine model, BALB/C mice were sensitized with Der p and were exposed to Der p via intranasal route during the challenge period. 1.8-Cineole was given by inhalation 6 h before the each challenge. Treatment with 1.8-cineole inhibited the Der p-induced cytokine protein expression, phosphorylation of p38 mitogen-activated protein kinase (MAPK) and Akt and intracellular TLR4 expression in HBECs. In the Der p-induced mouse model, airway hyper-responsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid (BALF) was also significantly reduced by 1.8-cineole treatment. The treatment of 1.8-cineole inhibited the increased production of interleukin (IL)-4, IL-13 and IL-17A in BALF after Der p challenge. These results suggest that 1.8-cineole suppresses Der p-induced IL-8, IL-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) production in HBECs. Finally, we confirmed that 1.8-cineole decreases AHR and eosinophilic airway inflammation in Der p-induced asthma mice.

Comparison of skin calming effects of cosmetic products containing 4-t-butylcyclohexanol or acetyl dipeptide-1 cetyl ester on capsaicin-induced facial stinging in volunteers with sensitive skin.

OBJECTIVE: To assess and compare the skin calming effect of cosmetic products containing 4-t-butylcyclohexanol (Eucerin(®) UltraSensitive Soothing Care Dry Skin) or acetyl dipeptide-1 cetyl ester (La Roche-Posay Toleriane(®) Ultra Intense Soothing Care) on subjective symptoms of skin sensitivity, a controlled, single-blind, randomized split-face capsaicin-induced stinging test was conducted. METHODS: Thirty-one female test subjects, ranging from 19 to 65 years of age, with self-perceived sensitive to very sensitive skin were enrolled. After a 3-day preconditioning period with no application of facial products and positive reaction to stimulation with a 40 ppm capsaicin cream, the test products were randomly applied to either the right or left nasolabial fold. Burning severity was assessed immediately after capsaicin application, and 1, 2, 5, 10 and 15 min after application of the test products. RESULTS: All 31 subjects reported a stinging/burning sensation on both nasolabial folds after application of capsaicin. Treatment with the 4-t-butylcyclohexanol containing product resulted in significant lower values for burning/stinging after one, and two minutes post-application in comparison to the values for the acetyl dipeptide-1 cetyl ester containing product. No significant difference was determined between the two test products for the point in time with most intense burning sensation, the severity of burning and the duration of burning after capsaicin application and subsequent application of the test products. CONCLUSION: Both products alleviated capsaicin-induced burning during the first 15 min after application. A faster and more pronounced soothing effect in vivo was demonstrated for the 4-t-butylcyclohexanol containing cosmetic product in comparison to the acetyl dipeptide-1 cetyl ester containing cosmetic formulation.

Skin compatibility and efficacy of a cosmetic skin care regimen with licochalcone A and 4-t-butylcyclohexanol in patients with rosacea subtype I.

BACKGROUND: Patients with rosacea often show facial sensitivity to cosmetics or skin care products that can influence the severity of symptoms and exacerbate erythema and inflammation. Nevertheless, special skin care is necessary to address cosmetic concerns and reduce the potential side-effects of topical or oral treatment of the disease. Appropriate skin care should comprise gentle cleansing, effective moisturization, soothing actives, UV protection and concealing pigments to help neutralize the appearance of redness. OBJECTIVE: To determine the compatibility and efficacy of a skin care regimen (consisting of a cleanser, a day care with SPF25 and a night care) containing licochalcone A (Lic A), an anti-irritant from the licorice plant Glycyrrhiza inflata, and 4-t-butylcyclohexanol (SymSitive(®) ), a substance which acts as a sensitivity regulator, in female subjects with clinically determined subtype I rosacea. METHODS: Thirty-two test subjects with mild to moderate rosacea used the skin care regimen daily for 8 weeks. Clinical assessment of erythema, subjective irritation and clinical photography were performed at baseline and after 4 and 8 weeks. Additionally, a quality-of-life questionnaire was filled out by the test subjects at baseline and week 8. The subjects completed a self-assessment questionnaire on product properties after 4 and 8 weeks of product use. RESULTS: Clinical assessments and subject response confirmed very good tolerability of the regimen, a statistically significant improvement in clinical grading for erythema and tactile roughness at weeks 4 and 8 and on telangiectasia at week 8 when compared to baseline scores. A statistically significant improvement in facial redness (a*) values, based on the L*a*b* colorimetric system, was determined at week 4 and 8 in comparison to baseline. No difference in corneometric measurement was detected at week 4 and 8 compared to baseline. CONCLUSION: The skin care regimen was found to be highly compatible with the sensitive facial skin of patients with rosacea subtype I and effective in improving signs of rosacea. Therefore, the daily use of skin care products containing LicA and SymSitive(®) in patients with rosacea improves the overall skin appearance and the quality of life of these patients.

Effective treatment for sensitive skin: 4-t-butylcyclohexanol and licochalcone A.

BACKGROUND: More than 50% of adults report to suffer from sensitive skin. This common condition is characterized by subjective sensations such as prickling, burning, skin tightness or pruritus, and is often accompanied by objective symptoms like inflammation and erythema. OBJECTIVE: The objective of this study was to develop an active ingredient concept for the treatment of sensitive skin. We tested compounds regarding their potential to (i) decrease the release of proinflammatory mediators, which among others induce erythema and (ii) counteract the hyperresponsiveness of nerve fibres and, thus, exert effects on cutaneous neurosensory dysfunction. METHODS: 4-t-butylcyclohexanol, licochalcone A and acetyl dipeptide-1 cetyl ester were analysed in vitro regarding their potential to (i) decrease the release of PGE2 and activation of NFκB and to (ii) inhibit TRPV1 activation or the release of neuronal CGRP. To assess subjective and objective symptoms of skin sensitivity in vivo, two controlled, single-blind, randomized studies were conducted with 4-t-butylcyclohexanol and the combination with licochalcone A. RESULTS: In vitro, 4-t-butylcyclohexanol significantly reduced TRPV1 activation, while acetyl dipeptide-1 cetyl ester had no effect on receptor activation. Licochalcone A significantly decreased NFκB signalling and PGE2 secretion, at lower concentrations than acetyl dipeptide-1 cetyl ester. A formulation containing 4-t-butylcyclohexanol showed a significant immediate anti-stinging/anti-burning effect in vivo, and a cream base containing a combination of 4-t-butylcyclohexanol and a licochalcone A-rich licorice extract reduced shaving-induced erythema. CONCLUSION: In vitro and in vivo data indicate that the combination of the TRPV1 antagonist 4-t-butylcyclohexanol and the potent anti-inflammatory licochalcone A provide an effective active ingredient concept for the treatment of sensitive skin, as the topical application resulted in an immediate relief from symptoms such as erythema and stinging.

Eucalyptol and Its Role in Chronic Diseases.

Patients with chronic diseases such as cardiovascular diseases, chronic respiratory diseases, and neurological diseases have been shown to benefit from treatments such as aromatherapy in addition to medication. Most chronic diseases are caused by chronic inflammation and oxidative stress as well as harmful factors. Eucalyptol (1,8-cineole), a terpenoid oxide isolated from Eucalyptus species, is a promising compound for treating such conditions as it has been shown to have anti-inflammatory and antioxidant effects in various diseases, including respiratory disease, pancreatitis, colon damage, and cardiovascular and neurodegenerative diseases. Eucalyptol suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production through the action of NF-κB, TNF-α, IL-1ß, and IL-6 and the extracellular signal-regulated kinase (ERK) pathway, and reduces oxidative stress through the regulation of signaling pathways and radical scavenging. The effects of eucalyptol have been studied in several cell and animal models as well as in patients with chronic diseases. Furthermore, eucalyptol can pass the blood-brain barrier and hence can be used as a carrier to deliver drugs to the brain via a microemulsion system. In summary, the various biological activities of eucalyptol such as its anti-inflammatory and antioxidant properties, as well as its physicochemical characteristics, make this compound a potentially important drug for the treatment of chronic diseases.

Differential co-expression and regulation analyses reveal different mechanisms underlying major depressive disorder and subsyndromal symptomatic depression.

BACKGROUND: Recent depression research has revealed a growing awareness of how to best classify depression into depressive subtypes. Appropriately subtyping depression can lead to identification of subtypes that are more responsive to current pharmacological treatment and aid in separating out depressed patients in which current antidepressants are not particularly effective. Differential co-expression analysis (DCEA) and differential regulation analysis (DRA) were applied to compare the transcriptomic profiles of peripheral blood lymphocytes from patients with two depressive subtypes: major depressive disorder (MDD) and subsyndromal symptomatic depression (SSD). RESULTS: Six differentially regulated genes (DRGs) (FOSL1, SRF, JUN, TFAP4, SOX9, and HLF) and 16 transcription factor-to-target differentially co-expressed gene links or pairs (TF2target DCLs) appear to be the key differential factors in MDD; in contrast, one DRG (PATZ1) and eight TF2target DCLs appear to be the key differential factors in SSD. There was no overlap between the MDD target genes and SSD target genes. Venlafaxine (Efexor™, Effexor™) appears to have a significant effect on the gene expression profile of MDD patients but no significant effect on the gene expression profile of SSD patients. CONCLUSION: DCEA and DRA revealed no apparent similarities between the differential regulatory processes underlying MDD and SSD. This bioinformatic analysis may provide novel insights that can support future antidepressant R&D efforts.

Speed of remission in elderly patients with depression: electroconvulsive therapy v. medication.

BACKGROUND: Severe depression can be a life-threatening disorder, especially in elderly patients. A fast-acting treatment is crucial for this group. Electroconvulsive therapy (ECT) may work faster than medication. AIMS: To compare the speed of remission using ECT v. medication in elderly in-patients. METHOD: The speed of remission in in-patients with a DSM-IV diagnosis of major depression (baseline MADRS score ≥20) was compared between 47 participants (mean age 74.0 years, s.d. = 7.4) from an ECT randomised controlled trial (RCT) and 81 participants (mean age 72.2 years, s.d. = 7.6) from a medication RCT (nortriptyline v. venlafaxine). RESULTS: Mean time to remission was 3.1 weeks (s.d. = 1.1) for the ECT group and 4.0 weeks (s.d. = 1.0) for the medication group; the adjusted hazard ratio for remission within 5 weeks (ECT v. medication) was 3.4 (95% CI 1.9-6.2). CONCLUSIONS: Considering the substantially higher speed of remission, ECT deserves a more prominent position in the treatment of elderly patients with severe depression.

How to switch to agomelatine after an unsuccessful try with paroxetine or venlafaxine.

OBJECTIVE/INTRODUCTION: The present trial informs clinicians about switching conditions with the antidepressant agomelatine after the failure of a treatment with either paroxetine or venlafaxine. METHODS: The total number of discontinuation-emergent symptoms, according to the Discontinuation-Emergent Signs and Symptoms checklist, was compared in double-blind conditions after 3 switching options: immediate substitution or initiation of agomelatine (25 mg/day p.o.) with either a short- or long-tapering of the previous drug. Secondary objectives included tolerability and safety assessments and the early clinical benefit after the switch. RESULTS: For all switching options, a withdrawal syndrome was observed 1 week after cessation of the selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) treatment. Psychic symptoms were the most frequently reported, and somatic symptoms were comparatively few. Early discontinuation symptoms after cessation of SSRI/SNRI treatment did not prejudice the antidepressant benefits of agomelatine over 8 weeks. CONCLUSIONS: Both abrupt and start-taper switching with agomelatine are options in everyday practice for those patients who have not responded to either paroxetine or venlafaxine. However, regardless of the switching strategy, the present double-blind study shows that early discontinuation symptoms that arise upon cessation of SSRI/SNRI can alter the patients' perception of the clinical benefit of the new antidepressant. Both practitioners and patients must be warned about these early discontinuation symptoms to prevent the symptoms from being confounded with a lack of therapeutic benefit of the new treatment.

Current use of drugs affecting the central nervous system for chemotherapy-induced peripheral neuropathy in cancer patients: a systematic review.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is common among cancer patients who undergo chemotherapy with platinum analogues, taxanes, vinca alkaloids, epothilone, bortezomib, and thalidomide. The purpose of this study was to investigate the evidence of using drugs affecting the central nervous system (CNS) to alleviate CIPN in cancer patients. METHODS: A systematic literature search was conducted using the CINAHL, EMBASE, and Medline databases to identify randomized controlled clinical trials (RCTs) reported in English up to 2013. We identified ten trials of CNS-acting drugs used to treat CIPN in cancer patients and reviewed efficacy and safety of CNS-acting drugs for CIPN using a standard data collection form. The risk of bias in each RCT was also assessed. RESULTS: Antidepressants were used in six studies and anticonvulsants in four studies. We found positive results for amitriptyline (topical), venlafaxine, and oxcarbazepine in one study each, but the results were not sufficient to draw definite conclusions. One trial with duloxetine showed a moderate effect (effect size, 0.513, P = .003) on CIPN pain relief. However, none of the results has yet been duplicated in an RCT with a large sample size. CONCLUSIONS: Insufficient RCTs exist to confirm the efficacy of CNS agents to reduce CIPN. This study highlighted the need for and the importance of conducting well-designed RCTs to generate evidence on CIPN symptom management. Additional RCTs are warranted to accelerate the potential use of CNS drugs for CIPN in cancer patients.

Open-longitudinal study of the effect of dissociative symptoms on the response of patients with panic disorder to venlafaxine.

The relationship between Panic Disorder (PD) and dissociation is well known. In this study we aimed to investigate whether or not dissociative experiences affect the response to PD drug treatment. For this purpose, standart dose of venlafaxine was preferred for treatment. 63 patients with PD were included in the study. Venlafaxine treatment with increasing dose was administered to each patient during a 10-week period. The Panic Disorder Severity Scale (PDSS) and the Dissociation Questionnaire (DIS-Q) were applied to the patients at the beginning of the study. Patients were divided into two groups based on DIS-Q scores. PDSS was applied again to both groups at the end of 10-week treatment. No difference between sociodemographic data and PDSS scores of two groups - patients with low DIS-Q scores (<2.5) and high DIS-Q scores (>2.5) - was found at the beginning. At the end of the study, a significant decrease in PDSS scores measured in both groups was detected. However, the decrease in PDSS score for the group with lower DIS-Q score was at a higher percentage (z=-3.822, p=0.0001). These results depict that dissociative symptoms accompanying PD affect psychopharmacological treatment in a negative way. Reevaluation of dissociative symptoms at the beginning and end of treatment would help in planning personal therapy.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults.

BACKGROUND: This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards tension-type headache prevention. Another updated review covers migraine. Tension-type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension-type headache. OBJECTIVES: To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension-type headache in adults. SEARCH METHODS: For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. SELECTION CRITERIA: We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older, of either sex, with tension-type headache. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension-type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period. MAIN RESULTS: The original review included six studies on tension-type headache. We now include eight studies with a total of 412 participants with chronic forms of tension-type headache. These studies evaluated five SSRIs (citalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) and one SNRI (venlafaxine). The two new studies included in this update are placebo controlled trials, one evaluated sertraline and one venlafaxine. Six studies, already included in the previous version of this review, compared SSRIs to other antidepressants (amitriptyline, desipramine, sulpiride, mianserin). Most of the included studies had methodological and/or reporting shortcomings and lacked adequate power. Follow-up ranged between two and four months.Six studies explored the effect of SSRIs or SNRIs on tension-type headache frequency, the primary endpoint. At eight weeks of follow-up, we found no difference when compared to placebo (two studies, N = 127; mean difference (MD) -0.96, 95% confidence interval (CI) -3.95 to 2.03; I(2)= 0%) or amitriptyline (two studies, N = 152; MD 0.76, 95% CI -2.05 to 3.57; I(2)= 44%).When considering secondary outcomes, SSRIs reduce the symptomatic/analgesic medication use for acute headache attacks compared to placebo (two studies, N = 118; MD -1.87, 95% CI -2.09 to -1.65; I(2)= 0%). However, amitriptyline appeared to reduce the intake of analgesic more efficiently than SSRIs (MD 4.98, 95% CI 1.12 to 8.84; I(2)= 0%). The studies supporting these findings were considered at unclear risk of bias. We found no differences compared to placebo or other antidepressants in headache duration and intensity.SSRIs or SNRI were generally more tolerable than tricyclics. However, the two groups did not differ in terms of number of participants who withdrew due to adverse events or for other reasons (four studies, N = 257; odds ratio (OR) 1.04; 95% CI 0.41 to 2.60; I(2)= 25% and OR 1.55, 95% CI 0.71 to 3.38; I(2)= 0%).We did not find any study comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. botulinum toxin) or non-drug therapies (e.g. psycho-behavioural treatments, manual therapy, acupuncture). AUTHORS' CONCLUSIONS: Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine (a SNRI) as preventive drugs for tension-type headache. Over two months of treatment, SSRIs or venlafaxine are no more effective than placebo or amitriptyline in reducing headache frequency in patients with chronic tension-type headache. SSRIs seem to be less effective than tricyclic antidepressants in terms of intake of analgesic medications. Tricyclic antidepressants are associated with more adverse events; however, this did not cause a greater number of withdrawals. No reliable information is available at longer follow-up. Our conclusion is that the use of SSRIs and venlafaxine for the prevention of chronic tension-type headache is not supported by evidence.

Differences in quality of life outcomes among depressed spinal cord injury trial participants.

OBJECTIVE: To assess the role that treatment response plays in a randomized controlled trial of an antidepressant among people with spinal cord injury (SCI) diagnosed with major depressive disorder (MDD) in explaining quality of life (QOL), assessed both globally as life satisfaction and in terms of physical and mental health-related QOL. DESIGN: Multivariable analyses were conducted, controlling for demographic, neurologic, and participatory factors and perceived functional limitations. SETTING: Rehabilitation centers. PARTICIPANTS: Of the 133 persons who were randomized into the Project to Improve Symptoms and Mood after Spinal Cord Injury randomized controlled trial, 124 participated in this study. All participants were between the ages of 18 and 64 years, at least 1 month post-SCI, met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for MDD, and completed the core measures used in this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Satisfaction with Life Scale and the physical and mental component summary scores of the Medical Outcomes Study 12-Item Short-Form Health Survey. RESULTS: Reduction in depressive symptoms over the course of a 12-week trial was predictive of increased QOL, which was measured as life satisfaction and mental well-being, within the context of other explanatory factors. However, reduction in symptoms did not explain differences in physical well-being among those with MDD. Perceived functional disability explained all 3 indices of QOL. CONCLUSIONS: Greater recognition has been given to QOL outcomes as endpoints of clinical trials because these often reflect participants' reported outcomes. Our findings support the association of QOL to the reduction of depression symptoms among trial participants. This association differs depending on how QOL is defined and measured, with stronger relations observed with life satisfaction and mental well-being among those diagnosed with MDD. The lack of association between depression and physical well-being may be explained by participants' subjective interpretation of physical well-being after SCI and their expectations and perceptions of improved physical health-related QOL based on the use of assistive technology. Consistent with our findings, pain is likely to play a role in decreasing physical QOL among those with incomplete injuries. Practicing caution is suggested in using physical well-being as an endpoint in trials among people with SCI.

Efficacy of venlafaxine XR for the treatment of pain in patients with spinal cord injury and major depression: a randomized, controlled trial.

OBJECTIVES: To (1) determine the efficacy of venlafaxine XR for the treatment of pain (secondary aim) in individuals with spinal cord injury (SCI) enrolled in a randomized controlled trial (RCT) on the efficacy of venlafaxine XR for major depressive disorder (MDD) (primary aim); and (2) test the hypothesis that venlafaxine XR would be effective for both neuropathic and nociceptive pain. DESIGN: Multisite, double-blind, randomized (1:1) controlled trial with subjects block randomized and stratified by site, lifetime history of substance abuse, and prior history of MDD. SETTING: Six Departments of Physical Medicine and Rehabilitation in university-based medical schools. PARTICIPANTS: Individuals (N=123) with SCI and major depression between 18 and 64 years of age, at least 1 month post-SCI who also reported pain. INTERVENTION: Twelve-week trial of venlafaxine XR versus placebo using a flexible titration schedule. OUTCOME MEASURES: A 0-to-10 numeric rating scale for pain, pain interference items of the Brief Pain Inventory; 30% and 50% responders. RESULTS: The effect of venlafaxine XR on neuropathic pain was similar to that of placebo. However venlafaxine XR resulted in statistically significant and clinically meaningful reductions in nociceptive pain site intensity and interference even after controlling for anxiety, depression, and multiple pain sites within the same individual. For those who achieved a minimally effective dose of venlafaxine XR, some additional evidence of effectiveness was noted for those with mixed (both neuropathic and nociceptive) pain sites. CONCLUSIONS: Venlafaxine XR could complement current medications and procedures for treating pain after SCI and MDD that has nociceptive features. Its usefulness for treating central neuropathic pain is likely to be limited. Research is needed to replicate these findings and determine whether the antinociceptive effect of venlafaxine XR generalizes to persons with SCI pain without MDD.

A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia.

WHAT IS KNOWN AND OBJECTIVE: Fibromyalgia is a painful disease affecting 1-2% of the United States population. Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and milnacipran, are well studied and frequently used for treating this disorder. However, efficacy data are limited for the SNRI venlafaxine despite its use in nearly a quarter of patients with fibromyalgia. Accordingly, we systematically reviewed the efficacy of venlafaxine for treatment of fibromyalgia. METHODS: PubMed, Web of Science and the Cochrane Database were searched using the terms 'venlafaxine' and 'fibromyalgia'. Results were classified as primary studies or review articles based on abstract review. References of review articles were evaluated to ensure no primary studies evaluating venlafaxine were overlooked. All clinical studies that investigated venlafaxine for the treatment of fibromyalgia were included and graded on strength of evidence. RESULTS AND DISCUSSION: Five studies met the inclusion criteria, including 4 open-label cohort studies and 1 randomized, controlled trial. Study durations ranged from 6 weeks to 6 months, and study sizes ranged from 11 to 102 participants. Four of the five published studies reported improvement in at least one outcome. Generally consistent improvements were observed in pain-related outcome measures, including the Fibromyalgia Impact Questionnaire (range, 26-29% reduction; n = 2 studies), Visual Analog Scale (range, 36-45% reduction; n = 2 studies), McGill Pain Questionnaire (48% reduction; n = 1 study) and Clinical Global Impression scale (51% had significant score change; n = 1 study). However, the few studies identified were limited by small sample size, inconsistent use of outcomes and methodological concerns. WHAT IS NEW AND CONCLUSION: Studies assessing the efficacy of venlafaxine in the treatment of fibromyalgia to date have been limited by small sample size, inconsistent venlafaxine dosing, lack of placebo control and lack of blinding. In the context of these limitations, venlafaxine appears to be at least modestly effective in treating fibromyalgia. Larger randomized controlled trials are needed to further elucidate the full benefit of venlafaxine.

The application of 1,8-cineole, a terpenoid oxide present in medicinal plants, inhibits castor oil-induced diarrhea in rats.

CONTEXT: 1,8-Cineole, a terpene, characterized as a major constituent occurring in the essential oils of several aromatic plants. It is widely used in pharmaceutical industry, as a food additive and for culinary purposes. OBJECTIVE: This study investigates the inhibitory effect of 1,8-cineole on transit time and diarrhea in animal models. MATERIALS AND METHODS: Acute toxicity and lethality of 1-8-cineole was determined by Lork's guidelines. The antidiarrheal effect of 1,8-cineole was investigated by determining the intestinal transit and enterpooling in rats. In all experiments, different doses of 1,8-cineole (20-120 mg/kg), atropine, and loperamide were administered orally. RESULTS: The LD50 of 1,8-cineole for oral administration was estimated to be 1280 mg/kg. 1,8-Cineole (20-120 mg/kg) did not show a significant decrease in small intestine transit (p > 0.05); however, the highest dose displayed a significant decrease in comparison with atropine (p < 0.05). This substance decreased the peristaltic index value to 68 ± 0.36% at a dose of 120 mg/kg compared with the control group (85.22 ± 4.31%) in the castor oil transit test. 1,8-Cineole significantly delayed the onset of diarrhea to -142.33 ± 6.08 min at 120 mg/kg, while the time was 103.66 ± 20.73 min for the control and >240 min for the loperamide. Moreover, 1,8-cineole significantly decreased intestinal fluid accumulation (p < 0.05). CONCLUSIONS: This study demonstrated antispasmodic and antisecretory activities of 1,8-cineole and rationalized the traditional use of the plant containing various levels of this terpene in the treatment of gastrointestinal complains such as diarrhea.

Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.