Discontinuation symptoms in depression and anxiety disorders

The present overview investigates whether different antidepressants have differing discontinuation symptoms upon treatment cessation, if these symptoms vary between depression and anxiety disorders, and with length of treatment. Data came from two comparative studies of escitalopram in major depressive disorder (MDD) (one vs. venlafaxine XR and one vs. paroxetine), two studies in social anxiety disorder (SAD) (one of which used paroxetine as the active reference), and one study in generalized anxiety disorder (GAD), using paroxetine as an active reference [total number of patients: escitalopram (n=1051); paroxetine (n=336); venlafaxine XR (n=124); placebo (n=239)]. All studies included a defined discontinuation period and used the Discontinuation Emergent Signs and Symptoms (DESS) checklist to record the number of discontinuation symptoms. All three antidepressants showed more discontinuation symptoms compared with placebo (p<0.001). Patients reported significantly fewer discontinuation symptoms with escitalopram than with paroxetine and venlafaxine XR in MDD (p<0.05). Escitalopram showed significantly fewer discontinuation symptoms than paroxetine in SAD (p<0.05) and GAD (p<0.001). For each antidepressant, no differences in discontinuation symptoms were observed between the three indications and there was no evidence for increased symptom incidence with increased length of treatment. Thus, discontinuation profiles differ between antidepressants of the same class and are broadly similar in different disorders. No evidence was seen for a higher discontinuation burden with longer treatment.     

The pharmacokinetics of standard antidepressants with aripiprazole as adjunctive therapy: studies in healthy subjects and in patients with major depressive disorder

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/ day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extended-release (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1:1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C( max) (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUC(TAU) (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.     

Efficacy and tolerability of venlafaxine versus specific serotonin reuptake inhibitors in treatment of major depressive disorder: a meta-analysis of published studies

Specific serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment in major depressive disorder (MDD). There is evidence that venlafaxine may be more effective than several antidepressants in the treatment of MDD. This meta-analysis includes all published, randomized, double-blind, head-to-head trials, which compared venlafaxine and an SSRI in the treatment of MDD in adults. Twenty-six trials comparing venlafaxine with an SSRI were included (total participants: 5858). Meta-analysis using a random effect model showed that venlafaxine was superior to SSRIs in achieving remission [odds ratio (OR)=1.13, 95% confidence interval (CI)=1.0-1.28, P=0.05] and response (OR=1.17, 95% CI=1.03-1.34, P=0.02). Subgroup analysis found that venlafaxine had a significantly better response rate than fluoxetine (OR=1.28, 95% CI=1.05-1.55, P=0.01). There were no significant differences in response or remission between venlafaxine and other individual SSRIs. There was no significant difference in all cause discontinuation between venlafaxine and SSRIs (OR=1.10, 95% CI=0.97-1.25, P=0.15). Venlafaxine had significantly higher discontinuation due to adverse events compared with SSRIs (OR=1.41, 95% CI=1.10-1.79, P=0.006). The superior efficacy of venlafaxine over SSRIs is of clinical importance. However, higher rates of discontinuation due to adverse events for venlafaxine compared with SSRIs are a disadvantage. Findings of this meta-analysis that included only published studies were similar to those from meta-analysis that included unpublished data.     

Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies

BACKGROUND: A substantial number of women of childbearing age suffer from depression. Despite this, relatively little is known about the safety of antidepressant use during pregnancy. PURPOSE: We conducted a meta-analysis of prospective comparative cohort studies to quantify the relationship between maternal exposure to the newer antidepressants and major malformations. METHODS: We searched Medline, Embase and Reprotox from 1996 to the present for studies comparing outcomes in first trimester exposures to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, reboxetine, venlafaxine, nefazodone, trazodone, mirtazapine and bupropion to those of non-exposed mothers. Data were combined using a random effects model; heterogeneity was tested with chi2, and publication bias with a funnel plot and the Begg-Mazumdar statistic. RESULTS: Twenty-two studies were identified, 15 were rejected (4 reviews, 4 without comparison groups, 2 third trimester exposures, 2 retrospective database studies, 2 case reports and 1 duplicate); 7 studies (n = 1774) met inclusion criteria. Effects were not heterogeneous (chi2 = 2.04, p = 0.92); funnel plot and test (tau = -0.24, p = 0.45) indicated no publication bias. The summary relative risk was 1.01 (95%CI: 0.57-1.80). CONCLUSIONS: As a group, the newer antidepressants are not associated with an increased risk of major malformations above the baseline of 1-3% in the population.     

Combining escitalopram with gaboxadol provides no additional benefit in the treatment of patients with severe major depressive disorder

The aim of this proof-of-concept study was to compare the efficacy of escitalopram (20 mg/d) in combination with fixed doses of gaboxadol to escitalopram (20 mg) in the treatment of patients with severe major depressive disorder (MDD). Adult patients were randomized to 8 wk of double-blind treatment with fixed doses of placebo (n=71), escitalopram (20 mg, n=140), escitalopram (20 mg)+gaboxadol (5 mg) (n=139), or escitalopram (20 mg)+gaboxadol (10 mg) (n=140). The pre-defined primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 8) in Montgomery-?sberg Depression Rating Scale (MADRS) total score using last observation carried forward (LOCF). There was no statistically significant difference in the mean change from baseline in MADRS total score between the 20 mg escitalopram+10 mg gaboxadol group and the 20 mg escitalopram group [difference=-0.45 MADRS points (95% CI -2.5 to 1.6, p=0.6619, full analysis set (FAS), LOCF, ANCOVA)] at week 8. The mean treatment differences to placebo at week 8 were -5.6 (95% CI -8.0 to -3.1, p<0.0001) (20 mg escitalopram), -5.1 (95% CI -7.5 to -2.7, p<0.0001) (20 mg escitalopram+5 mg gaboxadol), and -6.0 (95% CI -8.4 to -3.6, p<0.0001) (20 mg escitalopram+10 mg gaboxadol). The most common adverse events reported in the active treatment groups for which the incidence was higher than that in the placebo group, comprised nausea, anxiety and insomnia. There were no clinically relevant efficacy differences between a combination of escitalopram and gaboxadol compared to escitalopram alone in the treatment of severe MDD. All active treatment groups were superior in efficacy to placebo and were well tolerated.     

Efficacy of Venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine

This study evaluated the anxiolytic efficacy, safety and tolerability of a flexible dose of venlafaxine extended release (ER) compared with placebo and paroxetine in the short-term treatment of generalized social anxiety disorder (SAD). Adult outpatients with generalized SAD (n = 434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks. The primary efficacy variable was the Liebowitz social anxiety scale total score. Secondary efficacy variables included the patient-rated social phobia inventory and the proportion of responders in each group (a responder was defined as having a clinical global impression-improvement score of 1 or 2). Treatment with venlafaxine ER was associated with significantly greater improvement than treatment with placebo for all primary and secondary efficacy variables (p < 0.05). No significant differences in primary or secondary efficacy variables were observed between the venlafaxine ER and paroxetine groups. The week 12 response rates were 69%, 66% and 36% for the venlafaxine ER, paroxetine and placebo groups, respectively. Both active treatments were generally well tolerated and were associated with a similar incidence of adverse events. This study shows that venlafaxine ER is an effective, safe and well-tolerated drug treatment for SAD.     

The efficacy of selective serotonin reuptake inhibitors in adult social anxiety disorder: a meta-analysis of double-blind, placebo-controlled trials

Social anxiety disorder is associated with impairment in social and occupational functioning, significant personal distress and a possible economic burden, resulting in a reduction in quality of life. To understand better the efficacy of selective serotonin reuptake inhibitors in social anxiety disorder, randomized, double-blind, placebo-controlled trials were evaluated. Pubmed and PsychINFO electronic databases were searched for social anxiety disorder, social phobia, selective serotonin reuptake inhibitors, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Fifteen published, randomized, double-blind, placebo-controlled trials of selective serotonin reuptake inhibitors in social anxiety disorder were identified. Design, subject number, drug and dose, trial length, rating instruments, and baseline and end point data were extracted and then verified independently by a second investigator. Effect sizes were calculated from mean changes in drug and placebo groups in the Liebowitz Social Anxiety Scale and the Sheehan Disability Scale, as well as from other scales where available. For the binary data of the Clinical Global Impression of Change scores, Theta log-odds ratios (the effect-size measure appropriate for binary data) were calculated from proportion changes. Effect sizes for the Liebowitz Social Anxiety Scale ranged from -0.029 to 1.214. Effect sizes for the Sheehan Disability Scale ranged from 0.203 to 0.480 for work, 0.237 to 0.786 for social function, and 0.118 to 0.445 for family function. The Theta log-odds ratios for Clinical Global Impression of Change scores ranged from 0.644 to 3.267. Consistent with previous studies, selective serotonin reuptake inhibitors appear more effective than placebo for social anxiety disorder, with improvement extending into social and occupational function.     

An effect-size analysis of pharmacologic treatments for generalized anxiety disorder

Generalized anxiety disorder (GAD) is a prevalent and impairing disorder, associated with extensive psychiatric and medical comorbidity and usually characterized by a chronic course. Different drugs have been investigated in GAD; among them are the following: 1) SSRIs: paroxetine, sertraline, fluvoxamine and escitalopram; 2) SNRI1s: venlafaxine; 3) benzodiazepines (BZs): alprazolam, diazepam and lorazepam; 4) azapirones (AZAs): buspirone; 5) antihistamines (AHs): hydroxyzine; 6) pregabalin (PGB); and 7) complementary/alternative medicine (CAM): kava-kava and homeopathic preparation. We conducted an effect size (ES) analysis of 21 double-blind placebo-controlled trials of medications treating DSM-III-R, DSM-IV or ICD-10 GAD using HAM-A change in score from baseline or endpoint score as the main efficacy measure. Literature search was performed using MEDLINE and PsycINFO databases including articles published between 1987 and 2003 and personal communications with investigators and sponsors. comparing all drugs versus placebo, the ES was 0.39. Mean ESs, excluding children, were PGB: 0.50, AH: 0.45, SNRI: 0.42, BZ: 0.38, SSRI: 0.36, AZA: 0.17 and CAM: -0.31. Comparing ES for adults versus children/adolescents (excluding CAM) and conventional drugs versus CAM (excluding children/adolescents) we found significantly higher ES for children/adolescents and for conventional drugs (p < 0.001 and p < 0.01, respectively). No significant differences were found when comparing date of publication, location of site (i.e. US versus other), fixed versus flexible dosing, number of study arms, or number of outcome measures used. Medications varied in the magnitude of their ES, ranging from moderate to poor. Adolescents and children showed a much greater ES compared with adults. Subjects taking CAM had worse outcomes than placebo.     

Duloxetine: a review of its use in the treatment of major depressive disorder

Duloxetine (Cymbalta) is an orally administered, selective serotonin and noradrenaline reuptake inhibitor (SNRI) that has been approved for the treatment of major depressive disorder (MDD).Based on a considerable body of evidence, duloxetine at dosages ranging from 40 to 120 mg/day was effective in the short- and long-term treatment of MDD. Significant improvements versus placebo in core emotional symptoms as well as painful physical symptoms associated with depression, were seen in most, but not all, appropriately designed studies; results of meta-analyses suggested that improvements in these efficacy measures were apparent after 1-2 weeks' treatment with the highest recommended dosage of 60 mg once daily. Short-term (< or =15 weeks) administration of duloxetine at fixed or flexible dosages between 60 and 120 mg/day was noninferior to paroxetine 20 mg once daily, noninferior or inferior to escitalopram 10-20mg once daily, and had a similar global benefit-risk (GBR) profile to that of venlafaxine extended-release (XR) 150-225 mg/day in the treatment of MDD. Longer-term (6-8 months) treatment with duloxetine was similar in efficacy to paroxetine and escitalopram. Duloxetine is generally well tolerated, although it may be appropriate to avoid initiating treatment with the 60 mg/day dosage, as this has been associated with a higher discontinuation rate due to adverse events in some (but not all) comparative studies with escitalopram and venlafaxine XR.Definitive comparisons are awaited, although duloxetine seemingly provides a useful alternative to SSRIs and other SNRIs for the treatment of MDD. It also appears to be an attractive option for MDD patients presenting with painful physical symptoms.     

Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes based on a systematic review and meta-analysis of clinical trials

No systematic review or meta-analysis using a hard outcome has been conducted on the role of benzodiazepines for generalized anxiety disorder (GAD). The objective of this study was to assess the effectiveness and efficacy of benzodiazepines in the treatment of GAD based on trial drop-out rates. We used a systematic review of randomized controlled trials that compared any of the three best established benzodiazepines (diazepam, Lorazepam and aLprazolam) against placebo. Our primary outcome for effectiveness was withdrawal for any reason. Our secondary outcome tapping efficacy was withdrawal due to lack of efficacy, and that tapping side effects was withdrawals due to adverse events.We included 23 trials. Pooled analysis indicated less risk of treatment discontinuation due to lack of efficacy for benzodiazepines, compared to placebo, relative risk (RR) 0.29 (95% CI 0.18-0.45; p < 0.00001). Nevertheless, pooled analysis showed no conclusive results for risk of all-cause patient discontinuation, RR 0.78 (95% CI 0.62-1.00; p = 0.05). Meta-regression model showed that 74% of the variation in logRR across the studies was explained by year of publication (p <0.001).This systematic review did not find convincing evidence of the short-term effectiveness of the benzodiazepines in the treatment of GAD. On the other hand, for the outcome of efficacy, this review found robust evidence in favour of benzodiazepines. Due to the heterogeneity induced by year of publication, three hypotheses are plausibLe when it comes to being able to account for the differences between efficacy and effectiveness observed in the outcomes (publication bias, quality of the trial literature and a non-differential response to the placebo effect).     

Sustained response versus relapse: the pharmacotherapeutic goal for obsessive-compulsive disorder

Convincing evidence from placebo-referenced randomized controlled trials supports efficacy for clomipramine and selective serotonin reuptake inhibitors for acute treatment of obsessive-compulsive disorder. It remains less conclusively understood whether these agents maintain efficacy over the longer term. This paper systematically reviews long-term medication studies in obsessive-compulsive disorder. Studies of clomipramine, fluoxetine and sertraline investigated 'responders' from acute treatment trials and extended treatment up to 12 months versus placebo. Responses to medication were sustained. A 24-week placebo-controlled trial of escitalopram (10 mg or 20 mg/day) and paroxetine (40 mg/day) demonstrated ongoing efficacy for all three treatments. Studies that randomized treated cases to placebo demonstrated reemergence of symptoms in the placebo-treated cohort. Six relapse prevention trials were found by systematic search. Some, but not all, revealed significant advantages for remaining on medication. Paroxetine (20-60 mg/day) and escitalopram (10 or 20 mg/day) were each found to outperform placebo in preventing relapse during 24 weeks of double-blind, randomized follow-up. Meta-analysis, using Review Manager software (4.2.8), detected overall superiority of selective serotonin reuptake inhibitors to placebo in preventing relapse among adult treatment-responders. Worsening by five Yale-Brown Obsessive Compulsive Scale points emerged from the review as a suggested threshold for relapse. Viewed collectively, these results suggest that selective serotonin reuptake inhibitors are effective long-term treatments and relapse prevention represents the treatment target for obsessive-compulsive disorder.     

Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders

Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials. fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine < or = 300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine < or = 300 mg/day for > or = 8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dysfunction and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. CONCLUSION: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class.     

A comparison of the direct costs and cost effectiveness of serotonin reuptake inhibitors and associated adverse drug reactions

BACKGROUND: The economic burden of depression is known to be high and was estimated to be USD 83.1 billion in 2000. Serotonin reuptake inhibitors (SRIs), including both selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), have a superior adverse effect and safety profile relative to traditional agents (e.g. TCAs), and as a result have demonstrated superior cost effectiveness. Although efficacy across the SRIs is similar, the incidence of adverse drug reactions (ADRs) within SRIs remains significant and varies by agent. Patients who experience ADRs from SRIs may seek medical care, require additional treatment, and even discontinue treatment altogether, leading to increased utilisation and cost of therapy. OBJECTIVE: This study estimates the direct cost and cost effectiveness, taking into account the impact of treatment-related ADRs, of eight currently marketed SRIs (citalopram, escitalopram, generic fluoxetine, paroxetine, paroxetine controlled release [CR], sertraline, venlafaxine and venlafaxine extended release [XR]) used as initial treatment for depression. METHODS: A decision analytic model with a 6-month treatment goal was used to estimate the direct cost and cost effectiveness of treatment from the managed care/payer perspective. Estimates of SRI-related ADRs, associated treatments and costs were derived from the US FDA-approved prescribing information and published literature. Efficacy was assumed to be similar across all SRIs. Effectiveness was measured using quality-adjusted life years (QALY) based on EuroQol EQ-5D scores derived from the 2000 Medical Expenditure Panel Survey (MEPS). Censored least absolute deviations (CLAD) regression analysis was used to derive age-adjusted estimates of utility for all health states. Univariate and Bayesian second-order multivariate probabilistic sensitivity analyses were conducted to examine the impact of uncertainty in the parameter estimates. RESULTS: The expected direct cost and cost effectiveness of treatment from least to most expensive were: escitalopram (USD 3891; 0.341), citalopram (USD 3938; 0.340), generic fluoxetine (USD 4034; 0.335), venlafaxine XR (USD 4226; 0.336), sertraline (USD 4250; 0.335), generic paroxetine (USD 4385; 0.332), paroxetine CR (USD 4440; 0.332) and venlafaxine (USD 4613; 0.326). Monte Carlo simulation results suggested that escitalopram was the most likely (77%) to be cost effective for a willingness to pay < or = USD 50,000 per QALY, followed by citalopram (22%), generic fluoxetine (0.3%) and all other SRIs (0%). Sensitivity analyses indicated that the results of the study were robust to the assumptions underpinning the model. CONCLUSIONS: SRI-related ADRs have a significant impact on the direct cost and cost effectiveness of treatment. Escitalopram, with the lowest ADR rate of the SRIs, had the lowest expected treatment cost and greatest effectiveness when compared with citalopram, generic fluoxetine, generic paroxetine, paroxetine CR, sertraline, venlafaxine and venlafaxine XR.     

CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; chi 2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.     

What can we learn from Chinese randomized controlled trials? A systematic review and meta-analysis of Chinese venlafaxine studies

This systematic review evaluated Chinese trials examining the efficacy of venlafaxine in the treatment of depression. Chinese databases CNKI and VIP and western databases were searched for blinded randomized controlled trial publications comparing venlafaxine to other antidepressants or placebo (in English or Chinese). Trials had to establish diagnosis of depression according to the Chinese Classification of Mental Disorders, Diagnostic and Statistical Manual of Mental Disorders, or International Classification of Diseases. Studies were excluded if more than 20% of participants had a primary diagnosis of dysthymia or if more than 15% had a primary diagnosis of bipolar disorder. Effect sizes were calculated as Hedges' g for rating scale scores and Mantel-Haenszel risk ratios (MH RR) for response and remission data. Effect sizes were combined in a fixed-effects model. A total of 25 studies were included. Nine trials compared venlafaxine to selective serotonin reuptake inhibitor; placebo-controlled trials were lacking. Quality was at best modest, and all trials were underpowered. There were more responders (MH RR, 1.08; 95% confidence interval [CI], 1.02-1.15) and remitters (MH RR, 1.12; 95% CI, 1.02-1.24) in venlafaxine groups compared with those in tricyclic antidepressant group. Hamilton Depression Rating Scale end point scores in the venlafaxine groups were lower (Hedges' g = 0.16; 95% CI, 0.04-0.27), and venlafaxine was better tolerated than tricyclic antidepressant (Hedges' g = 0.56; 95% CI, 0.37-0.74). There were no significant differences between venlafaxine and selective serotonin reuptake inhibitor on any of these parameters. Analyses of publication bias were inconclusive. Chinese researchers have published a number of randomized controlled trials comparing venlafaxine to active comparators, but study quality was found to be low. To make optimal use of their research potential Chinese, researchers will have to improve trial reporting and the peer-review process.     

Fluvoxamine: new indication. No progress in obsessive-compulsive disorder

(1) Four drugs are approved in France for patients with obsessive-compulsive disorders, namely clomipramine and three selective serotonin reuptake inhibitors (SSRIs): fluoxetine, paroxetine and sertraline. None of the four has emerged as a reference treatment. For children with obsessive-compulsive disorder, the treatment hierarchy is as follows: psychotherapy; behaviour therapy; clomipramine; sertraline. (2) Fluvoxamine, another SSRI, has now been approved in France for the treatment of obsessive-compulsive disorder in patients aged at least 8 years, after European harmonisation of SPCs for fluvoxamine-based preparations. (3) In adults, two placebo-controlled trials and the six trials versus clomipramine show that fluvoxamine, like clomipramine, is only partially effective (about one-third of patients "respond"). (4) In the only placebo-controlled trial in 120 children and adolescents aged from 8 to 17 years, who were treated for 10 weeks, efficacy was even more modest (response rate 15%, compared to 10% with placebo). (5) The safety profile of fluvoxamine is the same as that of all SSRIs but it has a potential for more drug interactions. (6) In practice, approval of fluvoxamine in adults or children with obsessive-compulsive disorder will have no impact on their management.     

Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline- and methoxamine-evoked constriction of the dorsal hand vein

AIMS: To examine whether the antidepressant venlafaxine, a novel serotonin-noradrenaline re-uptake inhibitor (SNRI), can modify alpha-adrenoceptor-mediated venoconstriction in man. The effects of venlafaxine were compared with those of desipramine, a tricyclic antidepressant with noradrenaline uptake inhibiting properties, and paroxetine, a selective serotonin re-uptake inhibitor (SSRI), on noradrenaline-and methoxamine-evoked venoconstriction using the dorsal hand vein compliance technique. METHODS: Fifteen healthy male volunteers participated in five weekly experimental sessions. Each session was associated with a clinically effective dose of an antidepressant or placebo. The following oral dosages were used: venlafaxine 75 mg, venlafaxine 150 mg, desipramine 100 mg, paroxetine 20 mg, or placebo. A double-blind, cross-over, balanced design was used. In each session, dose-response curves to both locally infused noradrenaline acid tartrate (0.1-33.33 ng min-1 ) and methoxamine hydrochloride (0.5-121.5 microg min-1 ) were constructed. Systolic and diastolic blood pressure and pulse rate were measured in the supine and erect positions. Salivation was measured by the dental roll technique. RESULTS: Venlafaxine 150 mg and desipramine 100 mg potentiated the venoconstrictor response to noradrenaline (anova of log ED50s: P<0.01; individual comparisons: venlafaxine 150 mg vs placebo: P<0.005; mean difference, 95% CI: -0. 49 (-0.81, -0.17); desipramine 100 mg vs placebo: P<0.005; mean difference, 95% CI: -0.34 (-0.60, -0.09) without affecting the response to methoxamine. Neither paroxetine nor placebo had any effects on the venoconstrictor responses. Both doses of venlafaxine increased systolic blood pressure (supine and erect) and venlafaxine 150 mg increased diastolic blood pressure (supine) (anova, P<0.05). Desipramine increased heart rate (P<0.05). Desipramine and both doses of venlafaxine reduced salivation (P<0.025). CONCLUSIONS: These results show that, similarly to desipramine 100 mg, venlafaxine 150 mg can potentiate venoconstrictor responses to noradrenaline, consistent with venlafaxine's ability to block noradrenaline uptake in man. The importance of noradrenaline uptake blockade in these observations is confirmed by the lack of effect of the antidepressants on methoxamine-evoked venoconstriction and the failure of paroxetine to modify noradrenaline-evoked venoconstriction.     

A meta-analysis to evaluate the efficacy of statins in children with familial hypercholesterolemia

This meta-analysis was conducted to evaluate the effect of statins on the lipid profile in pediatric and adolescent patients with familial hypercholesterolemia (FH). Randomized, double-blind, controlled trials comparing statins with placebo were identified through electronic and manual search; percent reductions from baseline were calculated for various lipid parameters. Standardized mean differences (effect size) with 95% confidence interval (CI) were calculated for each study and pooled effect size was calculated. A total of 6 studies were included in the meta-analysis. As compared to placebo, statins caused a significant decrease in total cholesterol (TC) [-3.11% (95% CI -3.46 to -2.99)], low-density lipoprotein (LDL) [-4.01% (95% CI -4.27 to -3.81)], triglyceride (TG) [-1.41 (95% CI -1.66 to -1.26)] and a significant increase in high-density lipoprotein (HDL) [1.12 (95% CI 0.73 1.13)]. In conclusion, statins were shown to have good efficacy for the treatment of FH in children.     

Escitalopram : a review of its use in the management of major depressive and anxiety disorders

Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a commonly prescribed SSRI. The R-enantiomer is essentially pharmacologically inactive. Escitalopram 10 or 20 mg/day produced significantly greater improvements in standard measurements of antidepressant effect (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions Improvement and Severity scales [CGI-I and CGI-S] and Hamilton Rating Scale for Depression [HAM-D]) in patients with major depressive disorder (MDD) than placebo in several 8-week, placebo-controlled, randomised, double-blind, multicentre studies. Symptom improvement was rapid, with some parameters improving within 1-2 weeks of starting escitalopram treatment. In addition, escitalopram showed earlier and clearer separation from placebo than RS-citalopram, at one-quarter to half the dosage, in 8-week, placebo-controlled trials; had significantly better efficacy than RS-citalopram in a subgroup of patients with moderate MDD in a 24-week trial; and produced sustained response and remission significantly faster than venlafaxine extended release in patients with MDD. Escitalopram reduced relapse rate compared with placebo and increased the percentage of patients in remission in long-term trials (up to 52 weeks). Consistently significant improvements for all efficacy parameters were also observed in patients with generalised anxiety disorder, social anxiety disorder and panic disorder treated with escitalopram for 8-12 weeks in individual, randomised, placebo-controlled, double-blind investigations. The good tolerability profile of escitalopram is predictable and similar to that of RS-citalopram. Such adverse events as nausea, ejaculatory problems, diarrhoea and insomnia are expected but, with the exception of ejaculatory problems and nausea, which is mild and transient, these were generally no more frequent than with placebo in fully published clinical trials. No adverse events not previously seen in acute trials were reported with long-term use.CONCLUSIONS: Escitalopram, the S-enantiomer of RS-citalopram, is a highly selective inhibitor for the serotonin transporter, ameliorates depressive symptoms in patients with MDD at half the RS-citalopram dosage, has a rapid onset of symptom improvement and has a predictable tolerability profile of generally mild adverse events. Like RS-citalopram, escitalopram is expected to have a low propensity for drug interactions, a potential benefit in the management of patients with comorbidities. In combination, these properties place escitalopram, like other SSRIs, as first-line therapy in patients with MDD. Escitalopram is indicated for use in patients with panic disorder in Europe and, should further evidence confirm early findings that escitalopram reduces anxiety, the drug may well find an additional role in the management of anxiety disorders.