The FDA Alert on Serotonin Syndrome With Use of Triptans Combined With Selective Serotonin Reuptake Inhibitors or Selective Serotonin‐Norepinephrine Reuptake Inhibitors: American Headache Society Position Paper

(Headache 2010;50:1089‐1099) Background.— In 2006, a US Food and Drug Administration (FDA) alert warned about the potential life‐threatening risk of serotonin syndrome when triptans are used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). This American Headache Society Position Paper further reviews the available evidence of the potential risk of combining triptans with other serotonergic agents. Methods.— Using the Sternbach Criteria or the Hunter Serotonin Toxicity Criteria, the 29 cases used as the basis for the FDA alert were assessed in addition to a more recently published clinical review of 11 case reports of serotonin syndrome resulting from monotherapy, and one report of combination serotonergic agents. Evidence was evaluated according to the American Academy of Neurology Clinical Practice Guideline Process Manual. Results.— Collectively, 40 case reports are available in the literature for subjects receiving either combination or monotherapy of serotonin agonists, all of which are limited to Class IV level of evidence. Of the 29 cases used as the basis for the FDA alert, 10 cases actually met the Sternbach Criteria for diagnosing serotonin syndrome. No cases fulfilled the Hunter Criteria for serotonin toxicity. One case published since the original report does not meet either criteria, and subsequently reported cases involving triptan monotherapy include insufficient details to confirm a diagnosis of serotonin syndrome. Recommendations.— With only Class IV evidence available in the literature and available through the FDA registration of adverse events, inadequate data are available to determine the risk of serotonin syndrome with the addition of a triptan to SSRIs/SNRIs or with triptan monotherapy. The currently available evidence does not support limiting the use of triptans with SSRIs or SNRIs, or the use of triptan monotherapy, due to concerns for serotonin syndrome (Level U). However, given the seriousness of serotonin syndrome, caution is certainly warranted and clinicians should be vigilant to serotonin toxicity symptoms and signs to insure prompt treatment. Health care providers should report potential cases to MedWatch and consider submitting them for publication.     

Childhood abuse and treatment response in patients with irritable bowel syndrome: a post-hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release

Objective: Although irritable bowel syndrome (IBS) is frequently comorbid with childhood trauma, information on the clinical implications of this comorbidity is limited. We investigated whether a history of abuse was associated with response to treatment in a double blind, randomized, placebo controlled trial of paroxetine controlled release (CR) in IBS. Methods: Seventy‐two IBS subjects were randomized to receive paroxetine CR (dose 12·5–50 mg/day) or placebo for 12 weeks. Subject selection was independent of abuse history. Sixty‐one subjects completed the Sexual and Physical Abuse Questionnaire about their childhood abuse history. IBS symptoms were recorded using the Interactive Voice Response System (IVRS). Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Perceived Stress Scale (PSS) and Clinical Global Impression (CGI) were also measured. The primary outcome was treatment response defined as ≥25% reduction in composite pain scores (CPS) on the IVRS from randomization to end of treatment. Results: The rate of abuse history was 50·8% (n = 31/61). Baseline demographic clinical characteristics (CPS, BDI, BAI, PSS, CGI scores) were not associated with abuse history. After 12 weeks of treatment, subjects with abuse history showed significantly higher CPS (t = 2·422, P = 0·018) than subjects without a history and less mean change of CPS (t = 3·506, P = 0·001). In a logistic regression analysis, history of abuse did not predict treatment response as measured by ≥25% reduction in CPS (OR = 0·481, CI = 0·164–1·406, P = 0·181), while the drug status (paroxetine CR) was significantly associated with treatment response as defined by a CGI improvement score of 1–2 (OR = 12·121, CI = 2·923–50·271, P = 0·001). Abuse history did not predict CGI‐I (Fisher’s exact, P = 0·500) improvements during the trial. Conclusions: History of abuse did not appear to have any significant clinical correlates at baseline and did not predict treatment response. Further studies are needed to confirm whether SSRIs are effective in IBS patients irrespective of their abuse history.     

Rs 6313 polymorphism in 5‐hydroxytryptamine receptor 2A gene association with polysymptomatic primary nocturnal enuresis

Background: Tricyclic antidepressants (TCA) were used to treat nocturnal enuresis (NE) for decades of years although their real mechanisms are unknown. Recently, some case studies demonstrated the efficacy of selective serotonin reuptake inhibitors (SSRI) in the treatment of NE. Both TCA and SSRI have similar influences on serotonin transmission. This study was aimed at evaluating whether 5‐hydroxytryptamine receptor 2A (5HTR2A) gene is associated with NE. Methods: We analyzed rs6313 polymorphism in 5HTR2A gene of 213 Taiwanese children (116 NE cases and 97 healthy control subjects) using polymerase chain reaction‐restriction fragment length polymorphism. Results: There were no significant differences when comparing the genotypes and allelic frequencies of rs6313 polymorphism in 5HTR2A gene between patients with NE and control subjects. However, when subsequently comparing 5HTR2A genotypes and allelic frequencies in NE child with different phenotypes, genotypes TT and TC appeared higher risks of polysymptomatic NE compared with CC (odds ratio (OR)=10.71, 95% confidence interval (CI)=2.66–43.12; OR=2.68, 95% CI=0.67–10.75, respectively; P=0.0002); and allele T also revealed higher frequencies of polysymptomatic NE compared with allele C (OR=3.7, 95% CI=2.01–6.79, P=0.000015). Conclusions: This is the first study that shows the association between 5HTR2A gene polymorphisms and polysymptomatic NE. These results provide further evidence suggesting that genetic variations at 5HTR2A may influence NE treatment response. J. Clin. Lab. Anal. 24:371–375, 2010. © 2010 Wiley‐Liss, Inc.     

Treatment of depression in the elderly: A review of the recent literature on the efficacy of single- versus dual-action antidepressants

Background: Despite the prevalence of depression in the elderly, there is a shortage of randomized controlled studies comparing the efficacy of various antidepressant classes in this population.Objectives: This review of recent data on the treatment of depression in the elderly examined the relative efficacy of the selective serotonin reuptake inhibitors (SSRIs) and 2 antidepressant classes having broader neuroreceptor activity—the tricyclic antidepressants (TCAs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs). Tolerability was examined as a secondary objective.Methods: A systematic review of MEDLINE, PsycINFO, and PubMed (January 2003–January 2009) was performed using the terms antidepressant, SSRI, SNRI, TCA, depression, randomized controlled trials, human trials, and individual antidepressant names. The criteria for inclusion in the review were a doubleblind design, a placebo control or active comparator group, a population exclusively aged ≥59 years, and enrollment of patients with a diagnosis of major depressive disorder.Results: The literature search identified 18 trials of the treatment of depression in the elderly: 10 compared SSRIs either head to head or versus placebo, 2 compared TCAs with SSRIs, and 6 examined SNRIs (2 vs placebo, 1 vs a TCA, and 3 vs SSRIs). In 2 head-to-head trials, one of which measured efficacy in terms of change in Hamilton Depression Rating Scale (HAM-D) scores and response rates, and the other in terms of a preset 90% CI, TCAs and SSRIs had comparable efficacy. The data from 5 studies using various measures (including changes in Montgomery-Asberg Depression Rating Scale, HAM-D, or Geriatric Depression Scale [GDS] scores; response rates; and remission rates) suggested no additional efficacy benefit for the SNRI venlafaxine compared with SSRIs or TCAs. In a single trial, duloxetine was significantly more effective than placebo in terms of reductions in HAM-D and GDS scores (both, P < 0.001).Conclusion: The available data, although limited, suggest that the dual-action agents (TCAs and SNRIs) do not appear to confer any additional benefits in efficacy over single-action agents (SSRIs) in the treatment of depression in the elderly.     

Maintained cerebral metabolic ratio during exercise in patients with β‐adrenergic blockade

Background: Decreased cerebral metabolic ratio (CMR) [molar uptake of O₂ versus molar uptake of (glucose + ½ lactate)] during exercise is attenuated by intravenous administration of the non‐selective β‐adrenergic receptor antagonist propranolol. We evaluated to what extent cirrhotic patients in oral treatment with propranolol are able to mobilize brain non‐oxidative carbohydrate metabolism. Methods: Incremental cycle ergometry to exhaustion (86 ± 4·2 W; mean ± SD) was performed in eight cirrhotic patients instrumented with a catheter in the brachial artery and one retrograde in the right internal jugular vein. Healthy subjects form the control group. Results: In β‐blocked cirrhotic patients arterial lactate increased from 1·5 ± 0·3 to 5·1 ± 0·8 mM (P<0·05) and the arterial–jugular venous difference (a–v diff) from ?0·01 ± 0·03 to 0·30 ± 0·05 mM (P<0·05) at rest and during exercise, respectively. During exercise the glucose a–v diff of 0·46 ± 0·06 mM remained at a level similar to rest (0·54 ± 0·03 mM) and at exhaustion the CMR was not significantly changed (5·8 ± 1·1 versus 6·0 ± 0·6). In controls, CMR decreased from 5·6 ± 0·9 at rest to 3·4 ± 0·7 (P<0·05) during maximal exercise and at a lactate level comparable to that achieved by the patients it was 3·8 ± 0·4. Conclusion: During exhaustive exercise in cirrhotic patients the CMR is maintained and a significant cerebral uptake of lactate is demonstrated. The data suggest that oral treatment with a non‐selective β‐adrenergic receptor antagonist attenuates cerebral non‐oxidative metabolism.     

Semi‐quantitative tracking of intra‐airway fluids by computed tomography

Background: Airway secretions are a source of complications for patients with acute and chronic lung diseases, yet lack of techniques to quantitatively track secretions hampers research into clinical measures to reduce their pathologic consequences. Methods: In a preserved swine lung model, we tracked a contrasted mucus simulant (CMS) using sequential computed tomography (CT). Known drivers of secretion movement – gravity and ventilation – were tested. Ten millilitres of CMS were unilaterally introduced (1 ml min^?1) into the airways of 12 lung sets. After instillation, six lung sets were maintained prone and six were rotated 180°. Subsequently, all were mechanically ventilated for 10 min. CTs were obtained before infusion, after infusion and after ventilation ± rotation. For CT analysis, the lungs were partitioned into eight sub‐cuboids using anatomic landmarks. The volumes of two CT number ranges representing CMS and poor aeration/collapse were computed in every sub‐cuboid for each CT acquisition. Volume differences between study time points were used to quantify changes. Results: CMS and poor aeration/collapse volume change distributed gravitationally after infusion. After ventilation without rotation, the CMS and poor aeration/collapse volumes remained within the originally injected sub‐cuboid, although the poor aeration/collapse volume expanded (27·3 ± 6·1→50·5 ± 7·4 ml, P<0·05). After ventilation + rotation, there was a reduction in the CMS and poor/aeration collapse volumes in the originally injected sub‐cuboid (14·4 ± 1·7→4·4 ± 0·6 ml, P<0·05 and 18·3 ± 3·8→11·9 ± 2·7 ml, P<0·05, respectively) accompanied by increases in the gravitationally opposite sub‐cuboid (1·7 ± 0·2→11·1 ± 1·1 ml, P<0·05 and 0·8 ± 0·5→40·6 ± 3·5 ml, P<0·05, respectively). Conclusion: Movement of fluids within the bronchial tree can be semi‐quantitatively tracked with analysis of sequential CT acquisitions. In this isolated swine lung model, gravity had an important and brisk effect on movement of a viscous fluid, whereas ventilation tended to embed it peripherally.     

Functional near‐infrared spectroscopy to probe sensorimotor region activation during electrical stimulation‐evoked movement

This study used non‐invasive functional near‐infrared spectroscopy (fNIRS) neuroimaging to monitor bilateral sensorimotor region activation during unilateral voluntary (VOL) and neuromuscular electrical stimulation (NMES)‐evoked movements. Methods. In eight healthy male volunteers, fNIRS was used to measure relative changes in oxyhaemoglobin (O₂Hb) and deoxyhaemoglobin (HHb) concentrations from a cortical sensorimotor region of interest in the left (LH) and right (RH) hemispheres during NMES‐evoked and VOL wrist extension movements of the right arm. Results. NMES‐evoked movements induced significantly greater activation (increase in O₂Hb and concomitant decrease in HHb) in the contralateral LH than in the ipsilateral RH (O₂Hb: 0·44 ± 0·16 μM and 0·25 ± 0·22 μM, P = 0·017; HHb: ?0·19 ± 0·10 μM and ?0·12 ± 0·09 μM, P = 0·036, respectively) as did VOL movements (0·51 ± 0·24 μΜ and 0·34 ± 0·21 μM, P = 0·031; HHb: ?0·18 ± 0·07 μΜ and ?0·12 ± 0·04 μΜ, P = 0·05, respectively). There was no significant difference between conditions for O₂Hb (P = 0·144) and HHb (P = 0·958). Conclusion. fNIRS neuroimaging enables quantification of bilateral sensorimotor regional activation profiles during voluntary and NMES‐evoked wrist extension movements.     

Selective Serotonin Reuptake Inhibitor Use and Risk of Arrhythmia: A Nationwide,Population-Based Cohort Study

PurposeThis study compares the risks of arrhythmia among patients with depression receiving selective serotonin reuptake inhibitors (SSRIs) and those receiving other classes of antidepressants and among patients with depression receiving citalopram-escitalopram and those receiving other SSRIs.MethodsThis retrospective cohort study used data from the 2000–2011 National Health Insurance Research Database in Taiwan. Patients with depression who were new antidepressant users were included in the study sample. Propensity score matching was used to balance the covariates between the comparison groups. Crude incidence rates were generated by Poisson regressions, and Cox proportional hazards regression models were used to assess the rates of arrhythmia among SSRI users and nonusers of SSRI antidepressants as well as between citalopram-escitalopram users and users of other SSRIs.FindingsNeither SSRI (hazard ratio [HR] = 0.95; 95% CI, 0.83–1.08) nor citalopram-escitalopram (HR = 1.20; 95% CI, 0.95–1.51) exposure was associated with a risk of arrhythmia compared with other, newer non-SSRI antidepressants or noncitalopram SSRIs. An increase in mortality was, however, observed among citalopram-escitalopram users (HR = 1.21; 95% CI, 1.08–1.31).ImplicationsCitalopram, escitalopram, and other SSRIs were not associated with an elevated risk of arrhythmia compared with each other or with non-SSRI antidepressants. Nevertheless, citalopram and escitalopram were associated with an increase in mortality risk compared with other SSRIs and deserve further investigation.     

Endothelin‐1: increased plasma clearance,pulmonary affinity and renal vasoconstriction in young smokers

Pulmonary and renal haemodynamics and elimination of endothelin‐1 (ET‐1) were studied in six young smokers in response to 20 min intravenous infusion of ET‐1 (4 pmol kg^–1 min^–1) after smoking. At 20 min of ET‐1 infusion fractional ET‐1 extractions in the lungs and kidneys were 60 ± 2 and 60 ± 7%, respectively. Cardiac output and renal blood flow (RBF) fell by 18 ± 4% (P<0·05) and 34 ± 5% (P<0·01). Mean systemic arterial pressure increased (P<0·05) whereas pulmonary pressures were unchanged. Compared with previously published data in non‐smokers ( 38 , 39 ) basal arterial ET‐1 and ET‐1‐values during ET‐1 infusion were lower with a more rapid return to basal value. Smokers had higher pulmonary extraction of ET‐1 at the same pulmonary arterial concentration (P<0·05). RBF reduction was more pronounced (P<0·05). Systemic vascular resistance increased while pulmonary vascular resistance did not increase as in non‐smokers. Increased plasma clearance and more efficient pulmonary elimination of ET‐1 lowers the arterial level in young smokers. In addition ET‐1 evokes more pronounced renal vasoconstriction in these individuals.     

Doxycycline vs. levofloxacin in the treatment of community‐acquired pneumonia

Background: Community‐acquired pneumonia (CAP) affects 5–10 million adults annually in the United States with approximately 1·1 million hospitalizations. Current guidelines recommend fluoroquinolones as monotherapy for treatment of CAP in general medical wards and doxycycline monotherapy for outpatient therapy only. Fluoroquinolones are expensive and development of bacterial resistance to them has become a concern. Therefore, we studied whether doxycycline is as efficacious as levofloxacin in treatment of CAP in general medical wards. Methods: In this prospective double‐blinded trial, non‐pregnant adults with clinical and radiological evidence of pneumonia requiring hospitalization were enrolled. Patients who were septic, hypoxic requiring intubations, nursing home residents, diagnosed with severe hepatic or renal dysfunction, recently hospitalized or immunocompromised were excluded from the study. Subjects were randomly assigned to either i.v. levofloxacin 500 mg daily or doxycycline 100 mg twice daily. After discharge, patients were followed for 2 months. Results: There were 30 patients in the levofloxacin group and 35 patients in the doxycycline group. Groups were comparable in both clinical and laboratory profiles. Additionally, efficacy of treatment was not significantly different between the two groups (P = 0·844). Length of stay was 5·7 ± 2·05 days in the levofloxacin group and 4·0 ± 1·82 days in the doxycycline group (P < 0·0012). Failure rate was similar in both groups (P = 0·893). Total antibiotic cost was $122·07 ± 15·84 for levofloxacin and $64·98 ± 24·4 for doxycycline (P < 0·0001). Conclusions: Our study supports doxycycline as an effective and economical alternative therapy for levofloxacin in the empirical treatment of CAP in general medical wards.     

Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

Summary. Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. Objectives: To prospectively quantify the dose‐response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5‐HTTLPR) on platelet function. Methods: Nineteen drug‐free psychiatric outpatients (44.5 ± 10.8 years) were tested before and after 6 weeks of paroxetine treatment (20 mg day^?1). Based on clinical symptoms, paroxetine dosages were increased (40–50 mg day^?1) for 6 more weeks in 11 patients. Parameters related to platelet function were assessed by bleeding time, platelet function analyzer (PFA), platelet serotonin, platelet factor 4 (PF4), β‐thromboglobulin (β‐TG), and aggregation tests. Results: Paroxetine 20 mg day^?1 increased mean bleeding time by 1.2 min (95% confidence interval (95% CI) ?0.2–2.7) and reduced median platelet serotonin level (463 ng 10^?9 platelets; inter quartile range (IQR) 361–666), and platelet ß‐TG concentration (3.1 IU 10^?6 platelets; IQR 0.3–6.0). Other platelet parameters did not change significantly. Serial platelet aggregation tests did not become abnormal. Paroxetine dose‐escalation did not further influence platelet function. However, 5‐HTTLPR polymorphisms modified these effects: in L_A/L_A‐carriers, bleeding times did not change (?0.2 min; 95% CI ?0.6 to 0.9), while bleeding times significantly increased in <2L_A‐allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L_A‐alleles (868 ng 10^?9 platelets; IQR 585 to 1213) than in ≥1 L_A‐allele carriers (457 ng 10^?9 platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L_A‐alleles. Conclusions: Paroxetine 20 mg day^?1 does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ß‐TG. These paroxetine effects appear to be mediated by 5‐HTTLPR, with most pronounced effects in patients without L_A‐alleles.     

Temporal age‐related changes in spectral,fractal and complexity characteristics of heart rate variability

Cross‐sectional studies have suggested that heart rate (HR) variability, analysed using traditional time and frequency domain methods, is related to ageing, but no longitudinal studies have estimated the age dependence of HR fluctuation. This study evaluated temporal age‐related changes in 12‐h measures of HR variability among 109 patients with coronary artery disease (CAD), who underwent repeat Holter recordings at 32‐month intervals. Time and frequency domain measures, along with fractal and complexity measures of HR variability, were determined at the baseline and after 32 months. Changes in HR dynamics were compared with various laboratory variables, exercise data and angiographic progression of CAD. Traditional time and frequency domain measures of HR variability did not change significantly during the follow‐up, but the power‐law scaling slope decreased from ?1·29 ± 0·20 to ?1·36 ± 0·23 (P<0·01) and the short‐term fractal exponent (α₁) of HR dynamics from 1·29 ± 0·14–1·22 ± 0·18 (P<0·001). The approximate entropy value also decreased from 1·00 ± 0·19 to 0·95 ± 0·18 (P<0·05). The changes in HR behaviour were not related to demographic data, laboratory values or angiographic progression of CAD. Only a weak correlation was observed between the change in the power‐law slope and the baseline glucose value (P<0·05). This longitudinal study shows that the fractal characteristics of HR dynamics and the complexity properties of R‐R intervals undergo rapid changes along with ageing, and that fractal and complexity analysis techniques are more sensitive than traditional analysis methods in documenting temporal age‐related changes in HR behaviour.     

Components of the renin‐angiotensin‐aldosterone system in plasma and ascites in hepatic cirrhosis

Background Decompensated liver cirrhosis is characterized by activation of the renin‐angiotensin‐aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid. Methods In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites. Results Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = –0·73, P < 0·001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0·001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 ± 11%) was slightly lower than the albumin level (23 ± 8%), whereas the aldosterone level (43 ± 18%) was considerably higher (P < 0·0001). For renin and prorenin these percentages were much lower (P < 0·0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in‐vitro degradation rates of renin in plasma and ascitic fluid were identical. Conclusion In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites‐to‐plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.     

Simultaneous quantification of myocardial perfusion,oxidative metabolism,cardiac efficiency and pump function at rest and during supine bicycle exercise using 1‐11C‐acetate PET – a pilot study

Background: PET using 1‐¹¹C‐acetate (ACE‐PET) applied at rest is used for measuring absolute myocardial blood flow (MBF) and oxidative metabolic rate (k_mono). We evaluated the feasibility of quantitative ACE‐PET during exercise. Methods: Five endurance athletes underwent dynamic PET scanning at rest and during supine bicycle stress. Exercise was maintained at a workload of 120 Watt for 17 min. The rate‐pressure product (RPP) was recorded repeatedly. MBF, k_mono in left (LV) and right (RV) ventricular wall, cardiac output (CO), cardiac efficiency and a lung uptake value reflecting left heart diastolic pressures were calculated from the PET data using previously validated models. Results: MBF increased from 0·71 ± 0·17 to 2·48 ± 0·25 ml min^?1 per ml, LV‐k_mono from 0·050 ± 0·005 to 0·146 ± 0·021 min^?1, RV‐k_mono from 0·023 + 0·006 to 0·087 + 0·014 min^‐1, RPP from 4·7 ± 0·8 to 13·2 ± 1·4 mmHg × min^?1 × 10³ and Cardiac Output from 5·2 ± 1·1 to 12·3 ± 1·2 l min ^?1 (all P < 0·001). Cardiac efficiency was unchanged (P = 0·99). Lung uptake decreased from 1·1 ± 0·2 to 0·6 ± 0·1 ml g^?1 (P < 0·001). Discussion: A number of important parameters related to cardiac function can be quantified non‐invasively and simultaneously with a short scanning protocol during steady state supine bicycling. This might open up new opportunities for studies of the integrated cardiac physiology in health and early asymptomatic disease.     

Effects of hypocaloric very‐low‐carbohydrate diet vs. Mediterranean diet on endothelial function in obese women*

Background Obesity is a cardiovascular risk factor associated with endothelial dysfunction, but the effect of different weight loss strategies on endothelial function is not known. The effect of diet on endothelial function in two hypocaloric diets, a very‐low‐carbohydrate diet (A) and a Mediterranean diet (M), was measured by brachial artery flow‐mediated dilation (FMD). Design Using a longitudinal, randomized, open study design, subjects were engaged in a 2‐month weight loss diet. FMD, inflammatory cytokines [interleukin‐6 (IL‐6) and tumour necrosis factor‐α] and a marker of oxidative stress [8‐iso‐prostaglandin F2α (8‐iso‐PGF2α)] were measured in subjects on three occasions: before initiating the diet (T0), after 5–7 days of dieting (T5) and after 2 months of dieting (T60). The very short‐ and medium‐term time points were established to discriminate respectively the effect of the diet itself (T5) from that of weight loss (T60). Twenty overweight/obese but otherwise healthy women (BMI: 27–34·9 kg m^?2; age 30–50 years) completed the study. Results Group A lost more weight (mean ± SEM; ?7·6 ± 0·8 kg) than group M (?4·9 ± 0·6 kg, P = 0·014) at T60. The FMD was not significantly different between the two groups at T0 (group A: 12·2 ± 2·9% vs. group B: 10·3 ± 2·3%, P = ns). In group A, FMD was significantly reduced at T5 and returned to baseline at T60; in group M, FMD increased at T5 and returned to baseline at T60 (P = 0·007 for diet × time interaction). Serum concentrations of IL‐6 and 8‐iso‐PGF2α were not significantly different between the two groups at T0 and increased significantly at T5 only in group A (P < 0·001 and P < 0·005 respectively). Conclusion As endothelial dysfunction is known to be associated with acute cardiovascular events, this study suggests that the cardiovascular risk might be increased in the first days of a very‐low‐carbohydrate diet.     

Effects of escitalopram on sleep problems in patients with major depression or generalized anxiety disorder

Introduction  

Disturbed sleep is a key symptom in major depressive disorder (MDD) and generalized anxiety disorder (GAD). First-line antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs), may have different effects on sleep.     

Conventional treatment after myocardial infarction in routine clinical practice results in regression of left common carotid intima‐media thickness

This study aimed to evaluate the effect of standard medical treatment on the progression of atherosclerosis after a myocardial infarction, in an ordinary clinical setting, by measuring the right and left common carotid intima‐media thickness (IMT). The first investigation took place 3–12 months after the index event; the second took place 3·3–8·2 years after the first. In both investigations, the right and left carotid arteries of 102 patients were examined with an ultrasound duplex scanner. Common carotid IMT and calculated cross‐sectional intima‐media area (cIMa) were measured on both sides. More than 90% of the patients were treated with aspirin, beta‐blockers and statins. In the first investigation, IMT and cIMa were significantly greater on the left side compared to the right (IMT: 0·83 ± 0·22 and 0·74 ± 0·18 mm, P<0·001; cIMa: 18·2 ± 5·2 and 16·3 ± 5·1 mm², P<0·001). In the second investigation, IMT on the left side was significantly reduced compared to the first investigation (0·79 ± 0·22 and 0·83 ± 0·22 mm, P<0·05) with a corresponding tendency towards a decrease in cIMa on the same side. In our study, conventional medical treatment after a myocardial infarction in ordinary clinical routines resulted in regression of the common carotid IMT on the left side. The significant side difference in IMT emphasizes the importance of where and how the carotid IMT is measured in studies using this surrogate end point.     

C-QUALITY: Cost and Quality-of-Life Pharmacoeconomic Analysis of Antidepressants in Major Depressive Disorder in Italy

Introduction

Major depressive disorder (MDD) is a common and disabling condition across the world. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used antidepressants. The objective of this study was to assess the cost-effectiveness [€ per quality-adjusted life year (QALY)] of all SSRIs and all SNRIs for the treatment of MDD in Italy.

Methods

A decision analytic model was adapted from the Swedish Dental and Pharmaceutical Benefits agency model to reflect current clinical practice in the treatment of MDD in the largest Italian regions. This adaptation was possible thanks to the collaboration of an expert panel of Italian psychiatrists and health economists. The model evaluated patients with a first diagnosis of MDD and initiating an SSRI or an SNRI for the first time. The time horizon was 12 months. Efficacy and utility data for the model were retrieved from the literature and validated by the expert panel. Local data were considered for resource utilization and for treatment costs based on each regional health service perspective. Population-weighted regional data were used to define a national model. Scenario simulations, one-way sensitivity analyses, and Monte Carlo simulations were performed to test the robustness of the model.

Results

The base case analysis showed that escitalopram was associated with a lower total cost (€ 1,562) and a larger health gain (QALYs) at 1 year (0.732) per patient and dominated the other treatment strategies since more QALYs were achieved at a lower total cost. Sensitivity analyses support the robustness of the model.

Conclusion

The results indicate that escitalopram is the most cost-effective pharmacological treatment strategy for the Italian health service compared with other SSRIs and all SNRIs used in the first-line treatment of MDD.     

Morpho‐functional response of the elbow extensor muscles to twelve‐week self‐perceived maximal resistance training

The aim of this study was to determine morphological and functional changes of the elbow extensor muscles in response to a 12‐week self‐perceived maximal resistance training (MRT). Twenty‐one healthy sedentary young men were engaged in elbow extensor training using isoacceleration dynamometry for 12 weeks with a frequency of five sessions per week (five sets of ten maximal voluntarily contractions, 1‐min rest period between each set). Prior to, at 6 weeks and after the training, a series of cross‐sectional magnetic resonance images of the upper arm were obtained and muscle volumes were calculated. Maximal and endurance strength increased (P<0·01) by 15% and 45% at 6 weeks, and by 29% and 70% after 12 weeks compared with baseline values, while fatigue rate of the elbow extensors decreased by 67%. The volume of triceps brachii increased in both arms (P<0·01) by 4% at 6 weeks, and by 8% after 12 weeks compared with baseline values (right arm – from 487·4 ± 72·8 cm³ to 505·8 ± 72·3 cm³ after 6 weeks and 525·3 ± 73·7 cm³ after 12 weeks; left arm – from 475·3 ± 79·1 cm³ to 493·2 ± 72·7 cm³ after 6 weeks and 511·3 ± 77·0 cm³ after 12 weeks). A high correlation was found between maximal muscle strength and muscle volume prior (r² = 0·62) and after (r² = 0·69) the training (P≤0·05). A self‐perceived MRT resulted in an increase in maximal and endurance strength. Morphological adaptation changes of triceps brachii as a result of 12‐week specific strength training can explain only up to 26% of strength gain.