Placebos meta-analysis

Chick et al. (2003) conducted a meta-analysis that included data from 15 studies of acamprosate in an effort to determine whether acamprosate reduces the severity of relapse for patients in abstinence-oriented treatment who fail to abstain completely. Among patients who relapsed to drinking, acamprosate was significantly associated with less quantity and frequency of drinking, compared with placebo, at each of four follow-up periods (i.e., at 30, 90, 180, and 360 treatment days). During each of these periods, there were also fewer acamprosate-treated patients who drank an average of five or more drinks per day. 

A meta-analysis of placebo-controlled studies by Levin and Lehman (1991) showed that desipramine produced greater cocaine abstinence than placebo. Although a more recent review did not concur (Lima et al. 2001), secondary analyses of studies with imipramine, desipramine, and bupropion suggested that depressed cocaine abusers are more likely to show significant reductions in cocaine abuse than nondepressed cocaine abusers (Margolin et al. 1995 Nunes et al. 1991 Ziedonis and Kosten 1991). Furthermore, recent work with desipramine supported its efficacy in opioid-dependent patients, particularly in combination with contingency management therapies (Kosten et al. 2004 Oliveto et al. 1999). 

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... 

Covey LS, Classman AH A meta-analysis of double-blind placebo controlled trials of clonidine for smoking cessation. Br J Addict 86 991—998, 1991 Covey LS, Classman AH, Stetner F Naltrexone effects on short-term and long-term smoking cessation.] Addict Dis 18 31 0, 1999 Covey LS, Sullivan MA, Johnston A, et al Advances in non-nicotine pharmacotherapy for smoking cessation. Drugs 39 17-31, 2000 Dani JA, De Biasi M Cellular mechanisms of nicotine addiction. Pharmacol Biochem Behav 70 439 46, 2001... 

A recent meta-analysis was performed on all published human trials that used low-dose dopamine in the prevention or treatment of ARE20 A total of 61 studies were identified that randomized more than 3300 patients to low-dose dopamine or placebo. Results reveal no significant difference between the treatment and control groups for mortality, requirement for RRT, or adverse effects. 

Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2006 67 509-516. 

A recent meta-analysis evaluated patients at doses of 15 and 30 mg daily. Patients were analyzed for periods of 2 to 24 weeks. The majority of patients enrolled were female, and more than 80% of the patients evaluated received adjunctive modification in lifestyle. An average weight loss of 3.6 kg (7.9 lbs) was demonstrated for patients treated with phentermine compared with placebo. Although modest in amount, this value was statistically significant.37... 

In 1995 Guy Sapirstein and I set out to assess the placebo effect in the treatment of depression. Instead of doing a brand-new study, we decided to pool the results of previous studies in which placebos had been used to treat depression and analyse them together. What we did is called a meta-analysis, and it is a common technique for making sense of the data when a large number of studies have been done to answer a particular question. It was once considered somewhat controversial, but meta-analyses are now common features in all of the leading medical journals. Indeed, it is hard to see how one could interpret the results of large numbers of studies without the aid of a meta-analysis. 

The article that follows is a controversial one. It reaches a controversial conclusion - that much of the therapeutic benefit of antidepressant medications actually derives from placebo responding. The article reaches this conclusion by utilizing a controversial statistical approach - meta-analysis. And it employs meta-analysis controversially - by meta-analysing studies that are very heterogeneous in subject selection criteria, treatments employed, and statistical methods used. Nonetheless, we have chosen to publish the article. We have done so because a number of the colleagues who originally reviewed the manuscript believed it had considerable merit, even while they recognized the clearly contentious conclusions it... 

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. 

To answer this question, the regulators conducted their own meta-analysis of some of the data in their files. Their results were very similar to ours. They agreed that the average observed difference in improvement between drug and placebo is only about two points on the Hamilton scale, and their data also showed that most of the drug response could be explained as a placebo effect. Nevertheless, they argued that they had shown that the drugs were better than placebos, not only statistically, but clinically as well. 

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... 

When our most recent - and most definitive - meta-analysis was published, the headlines in many newspapers blazoned that antidepressants don t work .1 The Daily Telegraph headline phrased it more specifically, clarifying that antidepressants are no better than dummy pills ,2 but even this headline was not entirely accurate. What our analyses actually showed was that antidepressants work statistically better than placebos, but that this statistical difference was not clinically meaningful. It was too small a difference to be of much importance in the life of a severely depressed person. 

In 2001 two Danish researchers, Asbjorn Hrobjartsson and Peter Gotzsche, published an influential meta-analysis in which they estimated the difference between the effects of getting a placebo versus doing nothing at all.14 Although they found a significant placebo effect, especially in the treatment of pain, the overall effect seemed very small - much smaller than would have been expected of a powerful treatment. On the basis of these data, the researchers asked Is the placebo powerless and answered their own question by concluding that there was little evidence that placebos have powerful clinical effects. 

It seemed that Beecher was wrong after all. But was he There are two major problems with the Danish meta-analysis. One problem is the way in which the term placebo was defined. Usually, placebos are dummy pills, capsules or injections, presented in the guise of active medications. But many of the studies that Hrobjartsson and Gotzsche evaluated did not include a placebo in this sense of the term. Instead, these studies looked at the effects of leisure reading, answering questions about hobbies, and talking about books, movies and television shows. All of these were called placebos, and their effects were included... 

If you look back again at the graph in Chapter i (page 10) showing the results of the first meta-analysis that I published on the treatment of depression, you can see why people might conclude that psychotherapy - like antidepressants - is merely a placebo. My own analysis showed that the effectiveness of psychotherapy is about the same as that of drugs, and that although both are much better than no treatment at all, neither is much better than placebo pills.29... 

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... 

Linde, K. et al.. Are the clinical effects of homeopathy placebo effects A meta-analysis of placebo-controlled trials. Lancet, 350, 834,1997. 

Methodological controls. Some published studies on the effectiveness of hypericum have experimental design flaws, but there are several that are methodologically controlled, employing double-blind, randomization, and placebo controls. Randomized, placebo-controlled studies were summarized and evaluated in a meta-analysis by Linde and colleagues (1996). The combined subject pool was 1,757 outpatients with mild to... 

Lickey ME, Gordon B. (1991). Medicine and Mental Illness. New York W. H. Freeman and Company. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. (1996). St. John s wort for depression—an overview and meta-analysis of randomised clinical trials. BMJ. 313(7052) 253-58. Lingjaerde 0, Foreland AR, Magnusson A. (1999). Can winter depression be prevented by Ginkgo biloba extract A placebo-controlled trial. Acta Psychlatr Scand. 100(1) 62-66. 

Women have greater vulnerability for smoking-related diseases (specifically myocardial infarction and lung cancer) than men, but are less successful in quitting smoking (Harris et al. 1993 Zang and Wynder 1996 Thun et al. 2002 Henschke and Miettinen 2004 Henschke et al. 2006). Men benefit from nicotine replacement therapy more than women (reviewed by Perkins 2001). A recent meta-analysis of nicotine versus placebo patch studies has shown a significantly better response to nicotine in men than women (Perkins and Scott 2008). 

Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP (1998) Clinical effects of P-adrenergic blockade in chronic heart failure a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 98 1184-1191 Liggett SB (1999) Molecular and genetic basis of p2 a

receptor function. J Allergy Clin Immunol 104 S42-S46... 

Aspirin in the acute phase. The meta-analysis of the 1ST + CAST - - MAST studies has shown that aspirin (compared with placebo) reduces the rate of... 

St. John s wort is very popular as a physician-prescribed antidepressant in Europe and is widely used for this purpose—usually without medical guidance—in the United States. A meta-analysis of 23 studies concluded that St. John s wort was more effective than placebo in treating mild to moderate depression and was as effective as imipramine and standard antidepressants. It was also better tolerated than the antidepressants to which it was compared. A recent meta-analysis, however, failed to find St. John s wort effective for severe depression. 

---