Antidepressant trials meta-analyses

In order to study the possible association antidepressant drugs and adverse suicidal events in adult patients, FDA planned and conducted a meta-analysis study of randomized trials of antidepressants. The meta-analysis had several key features that supported its quality and utility for regulatory actions (1) hypotheses generated from previous and independent evidence provided the meta-analysis objectives (2) the meta-analysis was based on well-defined inclusion criteria and an exhaustive set of trials with patient-level data available (3) the meta-analysis employed rigorous and consistent outcome definitions across trials and patients and (4) the meta-analysis was based on prespecified statistical analysis plan. 

Kranzler HR, Bauer LO, Hersh D, et al Carbamazepine treatment of cocaine dependence a placebo-controlled trial. Drug Alcohol Depend 38 203-211, 1995 Levin FR, Lehman AF Meta-analysis of desipramine an adjunct in the treatment of cocaine addiction. J Clin Pharmacol 11 374-378, 1991 Lima MS, Reisser AA, Soares BG, et al Antidepressants for cocaine dependence. Cochrane Database Syst Rev 4 CD002950, 2001 Ling W, Shoptaw S, Majewska D Baclofen as a cocaine anti-craving medication a preliminary clinical study 0etter). Neuropsychopharmacology 18 403 04, 1998... 

In the decade that has passed since our article was published, the dust has settled around the issue of meta-analysis. It is no longer considered a controversial procedure. Meta-analyses of clinical trials are now routinely published in all of the top medical journals, and the National Institute for Health and Clinical Excellence (NICE), which publishes the treatment guidelines that are used by the NHS, crafts recommendations on the basis of meta-analyses that it conducts. Nevertheless, the editors were right about our article being controversial. Although some scholars in the field were persuaded by our analyses, others were sceptical, to put it mildly.2 The sceptics knew that antidepressants worked - if we had found otherwise, we must have done something wrong. Certainly there were other clinical trials of antidepressants beyond those that we had included in our analyses. Surely an analysis of those studies would point to a different conclusion. 

There were indeed clinical trials of antidepressants that we had not included in our meta-analysis, and there was also a meta-analysis of those other trials that had used some of the same methods we had used. It showed the same results that we had reported. The difference between drug and placebo in published trials of antidepressants was modest at best.3 Still, the controversy continued. 

In our meta-analysis, more than half of the clinical trials submitted to the FDA showed no difference between drug and placebo. Most reviewers of the clinical-trials literature have not had access to unpublished studies and may not even know of their existence. But the FDA and other regulatory agencies around the world knew of these data. Nevertheless, their existence is not even mentioned in the product labels, information leaflets and official Summaries of Product Characteristics (SPC) of most antidepressants. 

The most common criticism of our meta-analysis is the claim that the clinical trials we analysed were flawed, and that better results would have been found if the studies had been designed better. The trials were too short to show the real effect of antidepressants, the critics said. The people recruited to participate in them were not depressed enough, or they were too depressed. In any case, they were not representative of the patients who are generally seen in clinical practice. 

These continuation trials tell a very different story from that told by relapse-prevention trials. They show that there is little difference between antidepressant and placebo even when the clinical trial is extended over a longer period of time. Across the eight continuation trials that have been published, 79 per cent of patients on placebo and 93 per cent of patients on active medication remained well throughout the treatment period. In these long-term studies, placebo treatment was 95 per cent as effective as drug treatment. The authors of a meta-analysis of these trials concluded that the widely held - and probably erroneous - belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking .17... 

Many patients are excluded from clinical trials. Critics of our meta-analysis have suggested that antidepressants might work better for these patients than they do for those who are studied in clinical trials. Let us see how plausible this concern is. 

There seems to be considerable reluctance in some parts of the medical community to acknowledge the benefits of exercise in the treatment of depression. One meta-analysis of clinical trials showed that physical exercise was as effective as psychotherapy or antidepressant medication and much better than no treatment. But the authors concluded that the effectiveness of exercise in reducing symptoms of depression cannot be determined ,45 and the editors of the journal introduced the article with an editorial comment entitled effectiveness of exercise in managing depression is not shown by meta-analysis .46 Why not Because there were flaws in the way many of the studies had been designed. To be fair, there were indeed shortcomings in the studies, but these shortcomings also characterize clinical trials of antidepressants.47 If clinical trials like these do not establish the effectiveness of physical exercise as a treatment for depression, neither do they establish the effectiveness of antidepressants. 

Sneed, Joel R., Bret R. Rutherford, David Rindskopf, David T. Lane, Harold A. Sackeim and Steven P. Roose, Design Makes a Difference A Meta-Analysis of Antidepressant Response Rates in Placebo-Controlled Versus Comparator Trials in Late-Life Depression , American Journal of Geriatric Psychiatry 16, no. 1 (2008) 65-73... 

Another meta-analysis of placebo-controlled trials in depression published between 1980 and 2000 showed an increase in the response rates in the placebo arms of trials with a variety of antidepressants (Walsh et al.y 2002). Responses to placebo increased significantly in recent years, as shown by the high positive correlation with the year of publication. The association between response rate and year of publication was more statistically robust for placebo than for active medication. The change in placebo response rate did not appear to be explained directly by changes in study characteristics such as patient age, placebo lead-in or minimum required Hamilton Rating Scale for Depression score. A potential explanation could be the changing awareness of patients and the fact that many patients in recent clinical trials had been exposed to several previous treatments and thus expected to improve (see Box 5.4). 

In controlled trials, SRIs are better than placebo. All studies found these agents consistently and significantly more effective than standard antidepressants but each had a small sample size, and the results were not striking. Because of the consistency across studies, however, our meta-analysis with clomipramine was highly statistically significant. 

A number of studies indicate that some but not all antidepressants are effective in ADHD. Spencer and colleagues (66) found 29 studies (involving 1,016 patients) that supported the efficacy of TCAs in the treatment of ADHD. Desipramine is the TCA with the most efficacy data. Desipramine, based on a meta-analysis of five randomized trials involving 170 ADHD patients had efficacy (i.e., effect size) comparable with that of methylphenidate ( 90, 91). However, desipramine produced a higher rate of adverse effects compared with psychostimulants. Moreover, several sudden, unexpected deaths have been reported in children on desipramine ( 92,... 

The most recent systematic review and meta-analysis involved 37 randomized, double-blind, controlled trials (26 compared St. John s wort to placebo, 7 to tricyclic antidepressants, and 7 to selective serotonin reuptake inhibitors [SSRIs]). St. John s wort was reported to be more efficacious than placebo and equivalent to prescription reference treatments including the SSRIs for mild to moderate depression. Most trials used 900 mg/d (for mild to moderate depression) of St. John s wort for 4-12 weeks. 

Bech, R, Cialdella, P., Haugh, M. C., Birkett, M. A., Hours, A., Boissel, J. P., Tollefson, G. D. 2000, Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression, Br.J.Psychiatry, vol. 176, pp. 421 28. 

Moncrieff, J., Wessely, S., ffardy, R. 1998, Meta-analysis of trials comparing antidepressants with active placebos, Br.J.Psychiatry, vol. 172, pp. 227-231. 

The agency also provided us with a meta-analysis that showed that the estimated efficacy of antidepressants in children was minimal and likely to have been overestimated, because published studies have much more favorable results than unpublished studies. Thus, both clinical experience and published trials are likely to lead to inflated estimates of the efficacy of these drugs. 

Newman (2004) also found many unanswered questions The FDA s meta-analysis suggested that the new antidepressants double the risk of suicidality, about 2.5 percent to 5 percent, in trials lasting two or three months. But what happens if you take them for a year ... 

Furthermore, a meta-analysis of controlled trials did not point to a greater risk of suicide attempts or suicidal ideation with fluoxetine than with tricyclic antidepressants (1). 

This is an endogenous substance produced from adenosine triphosphate and the amino acid methionine. It is naturally involved in a range of biological processes. As a supplement, it is most studied in the treatment of depression, as well as treatment of liver disease. In a recent meta-analysis, doses of 400 mg-1600 mg per day were found to be superior to placebo and as efficacious as moderate-dose tricyclic antidepressants. A few small trials in patients with... 

Adenosyl methionine is most widely used for depressive disorders, and about 40 clinical trials have been carried out. A recent meta-analysis concluded that at 200-1600 mg/day it was superior to placebo, and with a global effect size ranging from 17%i to 38%i, it was as effective as tricyclic antidepressants. A later meta-analysis reported on 16 open uncontrolled trials, 13... 

A meta-analysis of 23 randomized, controlled trials of St. John s wort showed that the herbal extract is more effective than placebo for mUd to moderate depression, but that current evidence was inadequate to establish whether St. John s wort is as effective as standard antidepressants (2). In clinical trials, St. John s wort appeared to have fewer short-term adverse effects than some conventional antidepressants, but information on long-term adverse effects is lacking. 

Suicidal ideation has been described after 2-7 weeks of fluoxetine (17) and other case reports (SEDA-16, 9) (SEDA-17, 19). A causal link was initially questioned (SED-12, 57) (SEDA-15, 15) (SEDA-17, 19), and in one controlled trial there was no increase (SEDA-16, 9). Furthermore, a meta-analysis of controlled trials did not point to a greater risk of suicide attempts or suicidal ideation with fluoxetine than with tricyclic antidepressants (1). 

Over the years, both antidepressant and antipsychotic drugs have been used in the management of BN, with varying success. Meta-analysis of all the controlled clinical trials of pharmacotherapy published between 1980 and 1999, revealed that overall, such treatment led only to moderate initial improvement for the average patient (Nakash-Eisikovits et al. 2002). 

Kaizer E., Greenhouse J., Seltman H., Kelleher K. Do antidepressants cause suicidality in children A Bayesian meta-analysis. Clinical Trials, 2006 3 73-98. 

Bridge J A, Iyengar S, Salary CB et al. 2007. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment A meta-analysis of randomized controlled trials. JAMA 297(15) 1683-1696. 

Comparative rates of adverse effects with different antidepressants One limitation of meta-analyses is that they depend on the particular head-to-head comparisons chosen by the researchers, be they industry-based or academic-based. Multiple-treatments meta-analysis is a statistical technique that was developed to extract data from multiple randomized controlled trials to test for comparative efficacy and tolerability of agents that were not compared in individual reports. The relative efficacy and tolerability of 12 different antidepressants have been studied in a multiple-treatments meta-analysis, which showed that escitalopram, sertraline, bupropion, and citalopram were better tolerated than the other antidepressants studied The... 

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