Effectiveness and cost-effectiveness of antidepressants in primary care: a multiple treatment comparison meta-analysis and cost-effectiveness model

Objective

To determine effectiveness and cost-effectiveness over a one-year time horizon of pharmacological first line treatment in primary care for patients with moderate to severe depression.

Design

A multiple treatment comparison meta-analysis was employed to determine the relative efficacy in terms of remission of 10 antidepressants (citalopram, duloxetine escitalopram, fluoxetine, fluvoxamine mirtazapine, paroxetine, reboxetine, sertraline and venlafaxine). The estimated remission rates were then applied in a decision-analytic model in order to estimate costs and quality of life with different treatments at one year.

Data Sources

Meta-analyses of remission rates from randomised controlled trials, and cost and quality-of-life data from published sources.

Results

The most favourable pharmacological treatment in terms of remission was escitalopram with an 8- to 12-week probability of remission of 0.47. Despite a high acquisition cost, this clinical effectiveness translated into escitalopram being both more effective and having a lower total cost than all other comparators from a societal perspective. From a healthcare perspective, the cost per QALY of escitalopram was €3732 compared with venlafaxine.

Conclusion

Of the investigated antidepressants, escitalopram has the highest probability of remission and is the most effective and cost-effective pharmacological treatment in a primary care setting, when evaluated over a one year time-horizon. Small differences in remission rates may be important when assessing costs and cost-effectiveness of antidepressants.     

Comparison of escitalopram alone and combined with zolpidem in treating major depression and related sleep impairments

Escitalopram has been shown to be effective for treating major depression (MDD); however, research is lacking regarding its effect on treating MDD-related sleep impairments. The purpose of this study was to assess the efficacy of escitalopram monotherapy and investigate changes in insomnia, depressive symptoms, and quality of life (QOL). Participants were 14 patients with MDD who enrolled in a clinical trial at Jikei University Katsushika Medical Center. Escitalopram monotherapy was used, and hypnotics were administered three times per week for individuals suffering from sleep impairments. The following variables were assessed: (1) sleep quality [Pittsburgh sleep quality index (PSQI)], (2) depression [Zung self-rating depression scale (ZSRDS)], and (3) quality of life (QOL) as determined by the Sheehan disability scale (SDISS) and short form (36) health survey (SF-36). These assessments were conducted prior to any treatment (pre-test) and again 8–12 weeks after treatment (post-test). Monotherapy (E = escitalopram alone; n = 6) and combination therapy (E+ = escitalopram + zolpidem; n = 8) groups were compared. All participants completed the full protocol (average 9.4 ± 1.8 weeks). Regardless of treatment group, participants improved on all assessments (including sleep impairment). However, groups did not differ in their level of improvement. A two-factor ANOVA revealed that the E+ group showed particular improvements in QOL. In treating MDD and associated sleep impairments, zolpidem did not confer additional benefits. Thus, clinicians should consider E monotherapy for patients with MDD-related sleep impairments before prescribing combination therapies.

     

Safety of 80 antidepressants,antipsychotics, anti‐attention‐deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta‐review of 78 adverse effects

Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis­orders in this age group and are used not infrequently off‐label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta‐review, we systematically searched network meta‐analyses and meta‐analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications – including antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity disorder (ADHD) medications and mood stabilizers – in children and adolescents with mental disorders. We included data from nine network meta‐analyses, 39 meta‐analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti‐ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti‐ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti‐ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta‐review of top‐tier evidence regarding the safety of antidepressants, antipsychotics, anti‐ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.     

Effects of Venlafaxine and Escitalopram Treatments on NMDA Receptors in the Rat Depression Model

Depression may relate to neurocognitive impairment that results from alteration of N-methyl-D: -aspartate receptor (NMDAR) levels. Venlafaxine and escitalopram are two drugs commonly used to treat depression. The drugs may affect expression of NMDARs, which mediate learning and memory formation. The aim of the study was to examine whether the effects of venlafaxine and escitalopram treatments are associated with NMDARs in a rat model of depression. Forty male Wistar albino rats were randomly divided into four groups (n?=?10) as follows: control group, chronic mild stress group (CMS), venlafaxine (20?mg/kg body weight per day)?+?CMS, and escitalopram (10?mg/kg body weight per day)?+?CMS. After induction of depression, a decrease in the concentration of NR2B was observed; venlafaxine treatment prevented the reduction of NR2B expression. Escitalopram treatment did not effect the reduced levels of NR2B resulting from depression. There was no significant difference in NR2A concentration among groups. The present data support the notion that venlafaxine plays a role in maintaining NR2B receptor in experimental depression. It may be possible that treatment with escitalopram has no effect on NMDARs in experimental depression.     

Acquired hook-avoidance in the pike Esox lucius L. fished with artificial and natural baits

Tagged pike Esox lucius L. in a drainable pond were fished by hook and line, using either a spinner or a small live fish as bait. Catch per unit effort could be used as a measure for catchability because all captured pike were immediately returned to the pond and mortality was low.
Catchability to spinner fishing decreased to very low levels after about half of the population had been caught in this way. Catchability to live bait fishing remained unaffected both by intensive spinner and live bait fishing.
It was difficult to capture pike more than once by spinning. In live bait fishing, on the other hand, the number of recaptures closely matched the number expected if catchability remains unaffected by earlier capture.
The advantages are discussed of the use of artificial baits over live baits in hook and line fishing for pike.     

Selection for and initiation of continuous subcutaneous insulin infusion. Proceedings from a workshop

Continuous subcutaneous insulin infusion (CSII) has been used in the paediatric age group for more than 20 years. The technique is not yet widely used in most countries but there has recently been increasing interest in pump therapy for young children and adolescents. In 1999, 7.5% of Swedish children and adolescents with diabetes used pumps, now the figure is approaching 12%. The indication for starting pump therapy has usually been a medical problem, but today quality of life issues are becoming increasingly important. One technique sometimes used is to start CSII by wearing the pump only at night. Daily insulin requirements are usually decreased compared with injection therapy. Studies have shown that it is possible to lower HbA1c when using an insulin pump and that the risk of severe hypoglycaemia can be lowered. The use of CSII has also been successful in preventing recurrent admission for diabetic ketoacidosis. While starting pump therapy does take an extra effort from both the diabetes team and the family, routine visits are generally no more time-consuming than for patients on multiple injection therapy. CSII can be initiated during admission to hospital but most pumps are started on an outpatient basis. Our department has the patients on the day care ward for 3-4 days of 'pump school'. Parents wear a saline pump for practice. The total daily insulin dose is usually lowered 15-20% compared with multiple injections; on average 40-50% (sometimes up to 60%) of the daily dose is given as basal rate. We start all pumps on rapid-acting analogues and use 40 IU/ml if the basal rate is <0.3 IU/h. In conclusion, the use of CSII in children and adolescents is well accepted and can be managed safely.     

高效液相色谱串联质谱法同时检测粪便中三种抗抑郁药物*

目的:建立同时检测粪便中度洛西汀、氟西汀、艾斯西酞普兰三种抗抑郁药物的高效液相色谱串联质谱(HPLC-MS)方法。方法:样品经正己烷-异丙醇(95:5,v/v)预处理后,以超纯水和乙腈混合液作为流动相进行梯度洗脱,在Agilent ZORBAX SB-C18液相色谱柱(2.1 mm×100 mm,3.5 μm)上分离后用电喷雾串联质谱法检测,内标法定量。结果:粪便样品中度洛西汀、氟西汀、艾斯西酞普兰的加标回收率为61.6%～116.5%,精密度为 2.80%～12.9%(n=5),线性方程相关系数(r)均大于0.995,检出限分别为0.1 μg/g、1 μg/g、0.001 μg/g,定量限分别为0.5 μg/g、2 μg/g、0.005 μg/g,符合高效液相色谱串联质谱的分析要求。结论:该方法能够简单、准确检测出粪便中度洛西汀、氟西汀、艾斯西酞普兰这三种抗抑郁药的含量。     

Attention-deficit hyperactive disorder presenting with school truancy in an adolescent: a case report

Attention-deficit hyperactive disorder (ADHD) is a psychiatric illness commonly diagnosed during the early years of childhood. In many adolescents with undiagnosed ADHD, presentation may not be entirely similar to that in younger children. These adolescents pose significant challenges to parents and teachers coping with their disability. Often adolescents with behavioural problems are brought to medical attention as a last resort. This case describes an adolescent who presented to a primary care clinic with school truancy. He was initially treated for depression with oppositional defiant disorder and sibling rivalry. Only following a careful detailed history and further investigations was the diagnosis of ADHD made. He showed a positive improvement with the use of methylphenidate for his ADHD and escitalopram for his depression. The success of his management was further supported by the use of behavioural therapy and parenting interventions. There is a need to increase public awareness of ADHD, especially among parents and teachers so that early intervention can be instituted in these children.     

Management of vaginal dryness and dyspareunia in estrogen sensitive cancer patients

Cancer patients suffer from vaginal dryness and dyspareunia earlier and longer than the general population, with more severe and distressing symptoms. Life-style advices are the first step and vaginal lubricants can be tried, but they can't completely relieve atrophic symptoms. The most effective therapy is use of vaginal estrogens, but compliance and management are particularly difficult in estrogen sensitive cancer patients because of their systemic absorption. Compliance can be improved if they are begun at a very low dose and gradually increased until the lowest effective dose is reached. Promestriene only possesses an intramucosal effect, it can be used at very low doses in cancer patients suffering from urogenital symptoms.     

Do Media Use and Physical Activity Compete in Adolescents? Results of the MoMo Study

PurposeThe displacement hypothesis predicts that physical activity and media use compete in adolescents; however, findings are inconsistent. A more differentiated approach at determining the co-occurrence of physical activity and media use behaviors within subjects may be warranted. The aim of this study was to determine the co-occurrence of physical activity and media use by identifying clusters of adolescents with specific behavior patterns including physical activity in various settings (school, sports club, leisure time) and different types of media use (watching TV, playing console games, using PC / Internet).MethodsCross-sectional data of 2,083 adolescents (11–17 years) from all over Germany were collected between 2009 and 2012 in the Motorik-Modul Study. Physical activity and media use were self-reported. Cluster analyses (Ward’s method and K-means analysis) were used to identify behavior patterns of boys and girls separately.ResultsEight clusters were identified for boys and seven for girls. The clusters demonstrated that a high proportion of boys (33%) as well as girls (42%) show low engagement in both physical activity and media use, irrespective of setting or type of media. Other adolescents are engaged in both behaviors, but either physical activity (35% of boys, 27% of girls) or media use (31% of boys and girls) predominates. These adolescents belong to different clusters, whereat in most clusters either one specific setting of physical activity or a specific combination of different types of media predominates.ConclusionThe results of this study support to some extent the hypothesis that media use and physical activity compete: Very high media use occurred with low physical activity behavior, but very high activity levels co-occurred with considerable amounts of time using any media. There was no evidence that type of used media was related to physical activity levels, neither setting of physical activity was related to amount of media use in any pattern.     

Baseline Predictors of Success When Comparing Two Treatments

Since few medications are equally effective in all patients, physicians can maximize the risk/benefit ratio of therapy for their patients by limiting exposure based on baseline predictors of success. Traditional procedures typically evaluate the response of patients receiving the same treatment regimen without evaluating a comparator. However, when treatments are compared, such as in clinical trials, traditional procedures of identifying predictors must be modified to analyze the treatment effect on the primary outcome variable. We focus on clinical and statistical considerations that arise when developing baseline predictors through models which consider treatment differences. To illustrate an application of this method, we used data from 1,026 patients completing at least 6 months of double-blind therapy in clinical trials comparing fluoxetine (N=522) with placebo (N=504) for weight loss. Stepwise regression procedures were used to identify baseline variables which were predictive of a beneficial fluoxetine treatment effect on last-visit-carried-forward (LVCF) weight change. In this example, age, smoking activity, and uric acid concentration were the best baseline predictors of long-term treatment effect relative to LVCF weight change. Patients were more likely to achieve long-term benefit with fluoxetine if they were older, and/or were nonsmokers, and/or had high concentrations of uric acid at baseline. These predictors, developed through models keying on treatment effect, can be used to identify patients who are more likely to accrue benefits with active therapy beyond those expected with placebo therapy, thus enriching the treatment population so that a higher proportion of treated patients are successful.     

Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT_1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala.     

Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins.

Fluoxetine (Prozac) is an antidepressant that is thought to act by blocking presynaptic reuptake of the neurotransmitter serotonin. Despite widespread clinical use of fluoxetine, direct evidence for this mechanism has been difficult to obtain in vivo. We have determined that fluoxetine has an additional neuromuscular effect on C. elegans that is distinct from inhibition of serotonin reuptake. By screening for mutants resistant to this effect, we have identified seven genes. We report that two of these genes are homologous to each other and define a novel gene family that encodes over a dozen multipass transmembrane proteins. Our findings may have clinical implications for the mechanism of action of fluoxetine.     

Anti-TNF therapies in the management of acute and chronic uveitis

Patients with anterior uveitis may be treated with topical therapy alone but patients with posterior uveitis and those with sight threatening complications of anterior uveitis usually require systemic treatment especially if the disease is bilateral. The mainstay of treatment is corticosteroids and additional immunosuppressive agents such as cyclosporin and mycophenolate are used when necessary. There remains a significant cohort of patients in whom this therapy is either not tolerated or is ineffective. The use of the anti-tumour necrosis factor (TNF) antibodies has been very successful in controlling other immune-mediated disorders such as rheumatoid arthritis and has subsequently been extended to use in other arthritidies and other disorders such as psoriasis and Crohn's disease. TNF is known to play a key role in ocular inflammation as shown by animal studies and its detection in the ocular fluids of inflamed eyes in man. In some disorders all types of anti-TNF antibodies have similar efficacy but that does not appear to be the case with uveitis where infliximab is at present looking to be more effective than etanercept. The data on the use of anti-TNF drugs in uveitis is presented together with new data on its role as a steroid sparing agent.     

Corneal thickness in pseudoexfoliative glaucoma

Measurements of central cornea thickness (CCT) have a very important value in glaucoma patients; if the central cornea is thinner than it suggests, then the intraocular pressure is falsely low. This study compares the central cornea thickness between patients with pseudoexfoliative glaucoma, open angle glaucoma, angle closure glaucoma and control group. This study included 34 patients with pseudoexfoliative glaucoma, 31 patient with open angle laucoma, 28 patients with angle closure laucoma and 36 normal subjects in a control group. Patients in all groups and also normal subjects in control group had no other corneal disorders, no history of trauma, corneal surgery and were not patients with contacts lens use. Patients with pseudoexfoliative glaucoma and also patients with open angle glaucoma had significantly lower values of central cornea thickness compared with normal subjects in control group. Tomey EM 3000 is a non contact specular microscope which was used to measure central corneal thickness in this study. Pachymetry is an important method for diagnoses of glaucoma and for examination of the intraocular pressure in glaucoma patients, because values of the central corneal thickness affect the exact intraocular pressure readings.     

Fluoxetine increases extracellular levels of 3-methoxy-4-hydroxyphenylglycol in cultured COLO320 DM cells

Fluoxetine (Prozac) is a serotonin reuptake inhibitor. It increases extracellular levels of serotonin and is used in relieving the depressive symptoms of cancer patients. It has been reported that the drug may enhance the growth of certain cancer cells. This study investigates whether fluoxetine enhances the growth of a human colon cancer cell line (COLO320 DM) and if it affects the extracellular levels of serotonin or its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) and other monoamines and metabolites at two cell densities. The extracellular levels of serotonin, 5-HIAA and other monoamines and metabolites were measured simultaneously by high performance liquid chromatography from cell-culture media after incubation of cells both with and without fluoxetine for 3 days. The viability of COLO320 DM cells was evaluated using 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). At low cell densities (1.25x10(5) cells ml-1), fluoxetine at 1-10 microM significantly increased the extracellular levels of serotonin (p<0.005), 5-HIAA (p<0.005), and 3-methoxy-4-hydroxyphenylglycol (MHPG; p<0.001) as compared to the controls. Fluoxetine at 10-100 microM significantly inhibited the growth of COLO320 DM (p<0.005). At high cell densities (2x10(6) cells ml-1), fluoxetine at 1-10 microM significantly increased the extracellular levels of MHPG (p<0.01), and at 10 microM it significantly increased the extracellular levels of 5-HIAA (p<0.05). Fluoxetine at 100 microM significantly inhibited the growth of the cells (p<0.0001). These results suggest that fluoxetine at 1 microM of effective concentration may increase the extracellular levels MHPG, in addition to serotonin and 5-HIAA levels, yet not inhibit the growth of COLO320 DM.     

Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry

A gas chromatographic-mass spectrometric method is presented which allows the simultaneous determination of the plasma concentrations of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine after derivatization with the chiral reagent, (S)-(-)-N-trifluoroacetylprolyl chloride. No interference was observed from endogenous compounds following the extraction of plasma samples from six different human subjects. The standard curves were linear over a working range of 10 to 750 ng/ml for racemic fluoxetine and norfluoxetine and of 50 to 500 ng/ml for fluvoxamine. Recoveries ranged from 50 to 66% for the three compounds. Intra- and inter-day coefficients of variation ranged from 4 to 10% for fluvoxamine and from 4 to 13% for fluoxetine and norfluoxetine. The limits of quantitation of the method were found to be 2 ng/ml for fluvoxamine and 1 ng/ml for the (R)- and (S)-enantiomers of fluoxetine and norfluoxetine, hence allowing its use for single dose pharmacokinetics. Finally, by using a steeper gradient of temperature, much shorter analysis times are obtained if one is interested in the concentrations of fluvoxamine alone.     

Degradation of selected pharmaceutical and personal care products (PPCPs) by white-rot fungi

Today, more than 3,000 pharmaceutical and personal care products (PPCPs) are used and released into the environment at low doses but they are barely degraded in wastewater treatment plants. One of the potential alternatives to effectively degrade PPCPs is based on the use of white-rot fungi (WRF) and involves the oxidative action of extracellular fungal enzymes. The aim of this work is to study the potential ability of three WRF strains, an anamorph species of Bjerkandera sp. R1, Bjerkandera adusta and Phanerochaete chrysosporium, to degrade PPCPs belonging to different therapeutic groups: anti-depressants (citalopram and fluoxetine), antibiotics (sulfamethoxazole), anti-inflammatory drugs (diclofenac, ibuprofen and naproxen), anti-epileptics (carbamazepine), tranquilizers (diazepam) and fragrances (celestolide, galaxolide and tonalide). The results reported complete degradation of all the PPCPs except for fluoxetine and diazepam, which were partially removed in percentages from 23 to 57%. In the case of fragrances, these compounds were neither detected in the fungal cultures nor in the abiotic controls, indicating the possibility of volatilization during the experiment.     

Depression and suicidality in the adolescents in Osijek, Croatia

Mood disorders in children and adolescents and their treatments have received increasing attention and clinical investigation over the last few decades. The core features of mood disorders are essentially the same across the life span. Developmental level, however, appears to influence the expression of certain mood symptoms with greater frequency than other within the framework of depressive disorders. Suicide is the fourth leading cause of death in children between the ages of 10 and 15 years and the third leading cause of death among the adolescents and young adults 15-25 years. In this article the authors presents cross-sectional study done on the sample of 286 adolescents. Adolescents fulfilled self-rating scale Beck Depression Inventory for the screening of the depression and suicidality. In our sample 3.85% of the adolescents fulfilled the criteria for severe depressive episode and the 5.94% of the adolescents fulfilled criteria for moderate depressive episode. Also on the item of suicidality (Item 9) 0.7% of the adolescents had very high score, while 8.4 had significant score for the suicidal risk. Our results are in concordance with similar epidemiological studies done world while.