Meta-analysis of effectiveness and tolerability of treatment of mild to moderate depression with St. John's Wort

After anxiety, depression is one of the most common psychiatric diseases, showing a lifetime prevalence of 4.4 - 18 %. St. John's Wort is a herbal antidepressant combining a long tradition of use with well-proven medical research. We conducted a meta-analysis to review St. John's Wort's place in the treatment of depression. A comprehensive literature search was conducted for studies comparing effectiveness and tolerability of St. John's Wort with either placebo or synthetic antidepressant. Thirty studies met the inclusion as well as the quality criteria and were included in the meta-analysis. Four studies consisted of all three arms and were thus included in both analyses. Our results demonstrated a significant advantage for St. John's Wort compared to placebo (n = 2129, RR = 0.66, 95 % CI 0.57 - 0.78, p < 0.00001, NNT = 4.2 95 % CI 3.0 - 6.6, mean response: 53.3 vs. 32.7 %). Compared to synthetic antidepressants St. John's Wort demonstrated similar effectiveness (n = 2231, RR = 0.96, 95 % CI 0.85 - 1.08, p = 0.5, mean response: 53.2 % vs. 51.3 %). In the sub-group of mild to moderate depression, corresponding with the indication for St. John's Wort assigned by the German health authority, the herbal antidepressant showed better results against the synthetic antidepressants (n = 1166, RR = 0.85, 95 % CI 0.75 - 0.97, p = 0.01, NNT = 14.3, 95 % CI 8.3 - 100, mean response 59.5 vs. 52.9 %). This result viewed together with St. John's Wort's favourable side-effects profile, leading to a lower rate of drop-outs, suggests treatment with St. John's Wort should be attempted for milder forms of depression. Funnel plot analysis suggested publication bias could exist for the comparison with placebo. To put this in a perspective the fail-safe-N-test calculated that 423 studies with no effect would be needed to negate the presented result for placebo studies.     

Pharmacological treatment of adolescent major depression

Antidepressant agents are widely prescribed for adolescents, although specific data regarding their efficacy in this age range are limited. The aims of the present article are to review research findings regarding the use of antidepressant drugs for adolescent depression and to discuss the main results in light of our clinical experience. Only 13 controlled trials on the use of antidepressant drugs for adolescent major depression are available in the literature. Six studies evaluated the efficacy of tricyclic antidepressants, yet they only included 196 adolescents altogether. Seven studies, including a total of 1,403 patients, evaluated the efficacy of three specific serotonin reuptake inhibitors: fluoxetine, paroxetine, and sertraline. Based on published data, serotonin reuptake inhibitors appear to be the first-line psychopharmacologic treatment for adolescent depression, as three compounds (fluoxetine, paroxetine, and sertraline) appeared to be effective in this indication. Conversely, all published studies failed to demonstrate that the tricyclic antidepressants were superior to placebo. Several questions remain open and are discussed: How should we use available scientific data in clinical practice? Are there nonspecific factors implicated in treatment response? Is there a serotonin hypothesis for juvenile depression? What are the priorities for future research?     

Treatment of depression in children and adolescents

Depression occurs in children and adolescents, although it may appear differently in younger patients. Research suggests juvenile depression may respond to psychotherapy and to pharmacologic agents, and that antidepressants remain a valuable treatment for juveniles with depression. Diagnostic considerations in juveniles with mood symptoms are discussed. A brief overview is provided of the evidence supporting psychotherapy for juveniles with depression. Controlled antidepressant trials in juveniles with depression provide some support for the use of some selective serotonin reuptake inhibitors and little support for atypical antidepressants, tricyclic antidepressants, or monoamine oxidase inhibitors. Evidence from suicide rates over time, autopsy findings among juvenile suicides, and impacts of antidepressant prescribing trends are related to the current controversy over suicidality and antidepressant use in juvenile patients. Based on this evidence, practical guidelines for treatment of juvenile depression are provided.     

Antidepressants in child and adolescent depression: where are the bugs?

OBJECTIVE: To examine the data on the effect of antidepressant medication in depressed children and adolescents and the causes of the results obtained. METHOD: A systematic literature search was conducted, supplemented by a manual search, and a search of public online information on paediatric antidepressant trials reviewed by regulatory agencies. RESULTS: Data gathered from published and unpublished randomized controlled trials vary in their findings, with most of the studies showing a lack of efficacy characterized by a high placebo response rate. CONCLUSION: Differences from efficacy results with the same drugs in adult depression may be because of neurobiological developmental correlates, developmental differences in pharmacokinetics and pharmacodynamics, high rates of placebo response in children, and a number of methodological influences. There are several areas needing more attention in paediatric antidepressant clinical trials. Judicious use of published and unpublished studies to assess who may benefit from treatment with antidepressants seems warranted.     

抗抑郁药物治疗儿童青少年抑郁症的临床试验进展

本文目的是归纳并总结新型抗抑郁药物治疗儿童青少年抑郁症的效果和安全性,为儿童青少年抑郁症的药物干预提供参考。抑郁症是儿童青少年常见的精神疾病之一,严重影响患者的健康成长,可造成自杀等严重不良后果。使用抗抑郁药物是治疗儿童青少年抑郁症的重要手段,然而可用于儿童青少年的抗抑郁药物种类较少,临床应用受到一定限制。本文就近十年抗抑郁药物治疗儿童青少年抑郁症的临床试验进展进行综述。     

Efficacy and safety of antidepressants for treatment of depression in Alzheimer's disease: a metaanalysis.

OBJECTIVE: Depression in patients with Alzheimer's disease (AD) is common (15% to 63%) and is associated with significant morbidity and increased mortality. Our objective was to quantitatively summarize the data on the efficacy and safety of antidepressant treatment for depression complicating AD. METHOD: We performed a metaanalysis of randomized, double-blind, placebo-controlled trials of antidepressants with a database search of the English literature (up to 2006) and a manual search of references in the retrieved articles. We extracted the proportion of subjects who responded and remitted, experienced adverse events (AEs), discontinued treatment due to AEs, or discontinued treatment for any reason. Cognition scores were also extracted. RESULTS: We included 5 studies, which involved 82 subjects treated with antidepressants and 83 subjects who received placebo treatment. Antidepressants were superior to placebo for both treatment response (odds ratio [OR] 2.32; 95% confidence interval [CI], 1.04 to 5.16) and remission of depression (OR 2.75; 95% CI, 1.13 to 6.65). There were no significant differences between the 2 groups for change in cognition (weighted mean difference -0.71, 95% CI, -3.20 to 1.79), overall dropouts (OR 0.70; 95% CI, 0.29 to 1.66) or dropout due to AEs (OR 1.41; 95% CI 0.36 to 5.54). The numbers needed to treat for one additional AD patient to respond to antidepressant treatment were 5 (95% CI, 3 to 59) and 5 (95% CI, 2 to 24) for remission of depression. CONCLUSIONS: Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the potential side effects of antidepressants in this population.     

Efficacy of antidepressants in child and adolescent depression: a meta-analytic study

Summary. Objectives: To examine whether antidepressant drugs are superior to placebo in the treatment of juvenile depression. Method: Extensive literature search was done to retrieve all randomised controlled and all uncontrolled trials describing children and adolescents with a diagnosis of depression who underwent any antidepressant drug treatment. In order to combine results, separate analyses using random effect models were conducted first for controlled and then for both controlled and open studies. Results: 18 controlled and 23 open trials were submitted to meta-analysis. Tricyclics showed no significant benefit over placebo. Odds ratios for SSRIs were 1.84 (95% CI 1.35–2.50) for controlled and 1.83 (95% CI 1.40–2.40) for controlled and uncontrolled studies suggesting a significant benefit over placebo. Combining all antidepressants also gave confidence interval excluding the value one. Conclusions: Despite some promising data concerning the use of SSRIs in the treatment of adolescent depression, caution is warranted until the long-term safety of these agents can be demonstrated. Insufficient data are available to judge even the short term merits of these agents in prepubertal children. There is no evidence to support the use of tricyclics in this population.     

Stimulant Prescription Cautions: Addressing Misuse, Diversion and Malingering

Major depressive disorder (MDD) in children and adolescents is a public health problem that requires evidence-based management. Our objective is to review available studies, with a PubMed search, and briefly summarize safety and efficacy results of (mostly SSRI) antidepressants in children and adolescents with MDD. Fluoxetine and escitalopram are safe and effective in the treatment of MDD in children and adolescents both in reduction of symptoms, and in remission/response rates. However, response rates are lower than for non-OCD anxiety. Sertraline also had positive results in one study that pooled results from two studies. The number needed to treat (NNT) for MDD is 10, and the number needed to harm (NNH) for suicidality is 112. Methodological limitations in the studies include, mainly, high placebo response rates, associated with multiple study sites, younger patients, and lower MDD severity. Treatment should be maintained close to 1 year after remission, to prevent relapse. FDA-approved fluoxetine and escitalopram are safe and effective in the treatment of pediatric MDD. Sertraline also has some data supporting its efficacy and safety, but is not FDA-approved. The possible modest increase in suicidal ideation in some patients should be known by clinicians, but the risk/benefit ratio is 1 to 11.2 times favorable to using SSRIs in moderate to severe MDD.     

Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks

Objective: Long‐term antidepressant (AD) treatment for depression in bipolar disorder (BPD) patients is highly prevalent, but its benefits and risks remain uncertain, encouraging this meta‐analysis of available research. Method: We reviewed randomized controlled trials for BPD involving ≥6 months of treatment with AD ± mood stabilizer (MS) vs. placebo ± MS, using meta‐analyses to compare reported risks of new depression vs. mania. Results: In seven trials (350 BPD patients) involving 12 contrasts, long‐term treatments that included ADs yielded 27% lower risk of new depression vs. MS‐only or no treatment [pooled relative risk, RR = 0.73; 95% CI 0.55–0.97; number‐needed‐to‐treat (NNT) = 11], but 72% greater risk for new mania [RR = 1.72; 95% CI 1.23–2.41; number‐needed‐to‐harm (NNH) = 7]. Compared with giving an MS‐alone, adding an AD yielded neither major protection from depression (RR = 0.84; 95% CI 0.56–1.27; NNT = 16) nor substantial increase in risk of mania (RR = 1.37; 95% CI 0.81–2.33; NNH = 16). Conclusion: Long‐term adjunctive AD treatment was not superior to MS‐alone in BPD, further encouraging reliance on MSs as the cornerstone of prophylaxis.     

The role of provider attitudes in prescribing antidepressants to older adults: leverage points for effective provider education

OBJECTIVES: The purpose of this study was to determine if primary care provider knowledge of late-life depression, attitudes about treatment of depression in late life, and experience treating late-life depression affect the likelihood internists would prescribe antidepressants to older patients. METHODS: This study was a primary care provider survey study. From a pool of 456 eligible mailed surveys, 253 providers completed (55% response rate) a survey assessing provider self-reported knowledge about treating late-life depression with antidepressants, their attitudes about older patients' acceptance and response to antidepressant medications, their professional and personal experience with antidepressant medication, and their comfort with prescribing antidepressants to older patients was created for this study. RESULTS: Univariate analyses indicated that 75% of primary care providers were knowledgeable about the use of antidepressant treatment in older people, and 86% said they felt comfortable treating depression in older patients. Multivariate analyses indicated that the decision to treat older patients with antidepressants was largely influenced by time to treat patients, provider belief that antidepressants could treat late-life depression, their comfort with treating late-life depression, and having had older patients respond to antidepressant treatment in the past (R2 = .52, p < .001). CONCLUSIONS: This study shows that attitudinal and experiential factors play an important role in the likelihood that a provider will treat an older, depressed patient with an antidepressant, more so than knowledge about how to prescribe an antidepressant to older patients. Residency programs for primary care practitioners should include education about the efficacy of antidepressant treatment in older people and should involve hands-on experience in treating late-life depression.     

Are antidepressants effective in the acute and long-term treatment of depression? Sic et Non

The efficacy of antidepressant treatment of major depression remains a matter of controversy. A review of acute treatment studies suggests that for relatively more severe episodes of major depression, antidepressants are superior to treatment in the "placebo group;" however, there are numerous methodological confounds in the available literature. (Some recent, preliminary evidence suggests that antidepressants may also be of benefit in some less severely depressed populations).There is moderately strong evidence that, compared with placebo, maintenance antidepressant treatment reduces six-month relapse rates in major depression; however, it is less clear that antidepressants prevent actual recurrence of depression in the longer term. There is evidence of both over-use and under-use of antidepressant treatment, and there appears to be a "mismatch" between diagnosis and optimal treatment of depression in some clinical settings. Better designed studies are needed to resolve these uncertainties and to investigate such putative conditions as "oppositional tolerance" to long-term antidepressant treatment. The author advocates a conservative approach to antidepressant treatment, as well as a substantially extended "tapering" period when antidepressants are discontinued.     

A double-blind, randomized clinical trial to assess the augmentation with nimodipine of antidepressant therapy in the treatment of "vascular depression"

BACKGROUND: Cerebrovascular disease may cause "vascular depression" (VaD). Calcium channel-blockers are presumed treatments for cerebrovascular disease and might be expected to improve depression and prevent recurrence. OBJECTIVE: To examine the efficacy and tolerability of the use of nimodipine as an augmentation of fluoxetine in the treatment of VaD. DESIGN: A double-blind, randomized clinical trial in which 101 patients with VaD (Alexopoulos criteria) were treated with fluoxetine at standard doses. Patients were randomized to placebo (n=51) or nimodipine (n=50). Treatment outcomes were assessed using the Hamilton Depression Rating Scale (HDRS) regularly up to 8 months after treatment initiation. RESULTS: Depression was reduced in 63% of patients, but those whose treatment was enhanced with nimodipine had greater improvements overall by repeated measures analysis of covariance (ANCOVA) (F(1.80) = 9.76, p=0.001). In addition, a greater proportion of patients treated with fluoxetine-nimodipine (54% vs. 27%) exhibited full remission (chi2(d.f. 1)= 7.3, p = 0.006), with the number needed to treat (NNT) equal to 4 (95% CI 2-12). Of those experiencing full remission in the first 61 days, fewer patients on fluoxetine-nimodipine (3.7%) developed recurrence of major depression as compared to those on fluoxetine alone (35.7%) (chi2(d.f. 1) = 7.56, p = 0.006), NNT 3 (95% CI 2-9). Side-effects were noted in 33.3% of patients in the control group and 48% of the experimental group (chi2(d.f. 1) = 2.25, p = 0.133). CONCLUSIONS: In treating VaD, augmentation of fluoxetine with nimodipine led to better treatment results and lower rates of recurrence. These findings support the argument that augmentation of antidepressant therapy might be helpful in the treatment of cerebrovascular disease, which is involved in the pathogenesis of this type of depression.     

The contribution of pharmacoepidemiology to the antidepressant-suicidality debate in children and adolescents

A number of concerns have recently been raised about whether or not antidepressant medications are associated with suicidal thoughts and behaviour in children and adolescents. These concerns are based largely on results of meta-analyses of randomized, controlled trials (RCTs). Controversy exists about generalizing evidence from short-term RCTs, designed primarily to test efficacy outcomes, to routine practice settings. Pharmacoepidemiological studies complement RCTs by using observational methods to examine safety and effectiveness of medications in the general population. This article reviews the contribution of pharmacoepidemiology to the controversy surrounding suicide risk in children and adolescents taking antidepressants, noting how variations in study design and adjustment for potential confounding factors influence outcome.     

The contribution of pharmacoepidemiology to the antidepressant-suicidality debate in children and adolescents

A number of concerns have recently been raised about whether or not antidepressant medications are associated with suicidal thoughts and behaviour in children and adolescents. These concerns are based largely on results of meta-analyses of randomized, controlled trials (RCTs). Controversy exists about generalizing evidence from short-term RCTs, designed primarily to test efficacy outcomes, to routine practice settings. Pharmacoepidemiological studies complement RCTs by using observational methods to examine safety and effectiveness of medications in the general population. This article reviews the contribution of pharmacoepidemiology to the controversy surrounding suicide risk in children and adolescents taking antidepressants, noting how variations in study design and adjustment for potential confounding factors influence outcome.     

Patterns of antidepressant use among children and adolescents

OBJECTIVE: The purpose of this study was to identify patterns of new antidepressant use among children and adolescents and to determine whether the duration of treatment was sufficient. METHODS: A retrospective 12-month analysis was conducted of claims data for a cohort of nine- to 18-year-old new users of antidepressants in an Ohio Medicaid population. Treatment duration was categorized into five time intervals reflecting initial treatment through various continuation periods. RESULTS: A total of 554 children and adolescents started an antidepressant regimen during a three-month period. These children were mostly Caucasians (78 percent), and their average age was 13 years. Boys and girls were equally represented. The use of antidepressants increased with age among girls but declined among boys. The distribution of antidepressants dispensed was selective serotonin reuptake inhibitors, 47 percent; tricyclic antidepressants, 27 percent; and other antidepressants, 23 percent. The specific agent used varied by primary psychiatric diagnosis. The proportion of children who completed treatment was 94 percent for the four-week treatment period, 23.5 percent for the six-month period, and 12.6 percent for the whole year. CONCLUSIONS: Antidepressants are used in the treatment of children and adolescents who have a wide array of mental health problems. As with adults, continuation of treatment among children and adolescents declines dramatically after an initial period. In addition to studies of the clinical efficacy of antidepressant use among children and adolescents, future research is needed to assess adherence to practice guidelines and health outcomes in childhood and adolescent mental health.     

Treatment benefit and the risk of suicidality in multicenter, randomized, controlled trials of sertraline in children and adolescents

OBJECTIVE: The aim of this study was to examine the balance between the benefits of treatment and the risk of suicidality in children and adolescents in multicenter, randomized, controlled trials of sertraline versus placebo. METHOD: The published literature was searched for multicenter, randomized, placebo-controlled trials of sertraline for pediatric mental disorders. Four trials were identified: Two (pooled) in pediatric major depressive disorder (MDD; Wagner 2003) and two in obsessive-compulsive disorder (OCD; March et al. 1998; POTS Team 2004). Using intent-to-treat (ITT) analysis populations, the authors calculated the number needed to treat (NNT) for response and remission and the number needed to harm (NNH) for suicidality, and their ratio, for each clinical trial. RESULTS: NNTs ranged from 2 to 10, indicating clinically meaningful benefits. Benefit was greater for OCD than for MDD, and for adolescents as compared with children in MDD. No age effect was apparent for OCD. Suicidality was reported in 8 patients (5 assigned to sertraline and 3 assigned to placebo). All but 1 (a placebo-treated patient in the Pfizer OCD trial) were enrolled in the sertraline MDD trial. The NNH for suicidality in MDD was 64. Treatment emergent suicidality was more common in children (NNH 28.7) than in adolescents (NNH 706.3). Because no patient developed suicidality in sertraline-treated OCD patients, the NNH for sertraline in OCD approaches infinity. CONCLUSIONS: With the stipulation that doctor and patient preferences necessarily play a critical role in the choice of treatment, NNT to NNH ratios indicate a positive benefit-to-risk ratio for sertraline in adolescents with MDD and in patients of all ages with OCD.     

Paroxetine versus clomipramine in adolescents with severe major depression: a double-blind,randomized, multicenter trial

OBJECTIVE: To date, two randomized, double-blind trials of serotonin reuptake inhibitors (SRIs) have shown that antidepressant drugs are effective in treating adolescent depression. In contrast, tricyclic antidepressants (TCAs) are not superior to placebo. This has led to a serotonin hypothesis in this age group. This study explores this hypothesis and compares paroxetine, a specific SRI, with clomipramine, a TCA with SRI activity. METHOD: One hundred twenty-one adolescents (aged 12-20 years) with major depression were enrolled and randomized (stratified for age) to 20 or 40 mg of paroxetine or 75 mg or 150 mg of clomipramine for 8 weeks. Primary outcome measurements were the Clinical Global Impression (CGI) scale and the Montgomery and Asberg Depression Rating Scale (MADRS). RESULTS: Of the 121 patients, 58 received clomipramine and 63 paroxetine. Based on intent-to-treat analysis, both agents had similar efficacy, with no effect of age; 48.3% and 58.2% of the subjects receiving clomipramine and 65.1% and 59.3% of those receiving paroxetine were rated responders on the MADRS and CGI scales, respectively. Study withdrawals were frequent in both groups (41% and 31%, respectively), but side effects were significantly more frequent with clomipramine (69% versus 49.2%, respectively; p = .027). CONCLUSION: Paroxetine and clomipramine exhibit similar efficacy in adolescent depression. These data support the serotonin hypothesis but do not confirm it in the absence of a placebo arm. Given the adverse event profile of clomipramine, specific SRIs should be preferred. However, more placebo-controlled studies are needed to establish definitively the efficacy of SRIs in this age group.     

Pharmacotherapy of child and adolescent depression

Pediatric depression is a prevalent and recurrent condition that persists into adulthood and carries significant impairment, morbidity, and risk of mortality. Although there has been a surge of pediatric antidepressant studies in recent years, depression remains largely understudied, unrecognized, and untreated in children and adolescents. Few antidepressant trials have yielded positive results in pediatric depression. Regulatory agencies recently issued warnings against the use of selective serotonin reuptake inhibitors and newer antidepressants in depressed children and adolescents because of a possible link between their use and the appearance or worsening of suicidal ideation or attempts. The authors review data on efficacy and safety of antidepressants for the treatment of pediatric depression to provide treating clinicians with a basis on which to guide their treatment recommendations.     

Pharmacotherapy in depressed children and adolescents

In children and adolescents, antidepressants are used in the treatment of depressive symptoms and several other psychiatric conditions. In the treatment of mild and moderate depressive symptoms, non-pharmacological approaches such as psychotherapy play a major role, a severe symptomatology may demand a combination with antidepressants. As first-choice medication for the treatment of juvenile depression, the selective serotonin reuptake inhibitor (SSRI) fluoxetine is recommended, due to its efficacy and approval. As second-choice antidepressants the SSRIs sertraline, escitalopram and citalopram might be used. Other antidepressants - such as tricyclic antidepressants, α(2)-adrenoceptor antagonists, selective noradrenalin reuptake inhibitors (SNRI) - may be alternatively used, but not as first- or second-choice medications. In the case of "off-label" use, patients and parents have to be carefully informed prior to the start of medication, after a thorough risk-benefit analysis. In the following overview we address a general framework, therapeutic strategies and the issues of antidepressant pharmacotherapy for the treatment of unipolar depression in childhood and adolescence.